KR100940619B1 - Macrocyclic hepatitis C serine protease inhibitors - Google Patents

Macrocyclic hepatitis C serine protease inhibitors Download PDF

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KR100940619B1
KR100940619B1 KR20057014600A KR20057014600A KR100940619B1 KR 100940619 B1 KR100940619 B1 KR 100940619B1 KR 20057014600 A KR20057014600 A KR 20057014600A KR 20057014600 A KR20057014600 A KR 20057014600A KR 100940619 B1 KR100940619 B1 KR 100940619B1
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KR20050111585A (en
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수안네 나카지마
젠웨이 미아오
잉 선
구오유 슈
야트 선 오르
즈헤 왕
프랭크 우
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이난타 파마슈티칼스, 인코포레이티드
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Priority to US10/365,854 priority
Priority to US10/384,120 priority patent/US20040180815A1/en
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D513/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08Tripeptides
    • C07K5/0802Tripeptides with the first amino acid being neutral
    • C07K5/0804Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Abstract

The present invention relates to compounds of formula (I), (II) or (III), pharmaceutically acceptable salts, esters or prodrugs, wherein W is a substituted or unsubstituted heterocyclic ring system. The compound inhibits serine protease activity, in particular hepatitis C virus (HCV) NS3-NS4A protease. The compounds of the present invention thus interfere with the life cycle of hepatitis C virus and are also useful as antiviral agents. The invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating HCV infection in a subject by administering a pharmaceutical composition comprising a compound of the invention.
Figure 112005043726247-pct01023
Figure 112005043726247-pct01024
Figure 112005043726247-pct01025
(I) (II) (III)
Hepatitis, Protease, Arylalkyl, Heterocycloalkyl, Alkynyl, Aryl

Description

Macrocyclic hepatitis C serine protease inhibitors

[Reference to Related Applications]

This application has been filed on February 13, 2003. (Change of US 10 / 365,854); Filed February 7, 2003 (Change of US 10 / 360,947); And (Changes in US 10 / 384,120), each of which is incorporated herein by reference for specific purposes.

The present invention relates to novel macrocycles that have activity against hepatitis C virus (HCV) and are also useful for the treatment of HCV infection. More particularly, the present invention relates to macrocyclic compounds, compositions containing such compounds and methods of using the same as well as methods of making such compounds.

HCV is a major cause of non-A and non-B hepatitis, and is also an increasingly serious public health problem in the developing and developing world. More than 20 million people worldwide are estimated to be infected with the virus, surpassing nearly four times the population infected with human immunodeficiency virus (HIV). Because of the high percentage of individuals suffering from chronic infection, HCV-infected patients are at high risk of developing cirrhosis of the liver, subsequent hepatocellular carcinoma and terminal cancer. HCV is the leading cause of hepatocellular carcinoma and the cause of patients requiring liver transplantation in the western world.

There are significant obstacles to the development of anti-HCV therapies. Examples include, but are not limited to, the resistance of the virus, the diversity of the virus during replication in the host, the high frequency of virus-producing drug resistance variants, the lack of replicable infectious culture systems of HCV replication and murineism, and small animal models. do. In most cases, given a mild course of liver infection and complex biology, great care should be taken with antiviral drugs that are likely to have significant side effects.

Only two approved therapies for HCV infection are currently available. The first area of treatment generally includes a 3-12 month course of intravenous interferon-α (IFN-α), while the newly approved second generation treatment is concurrent with common antiviral nucleotide analogs such as IFN-α and ribavirin. Includes treatment. Both of these treatments suffer from interferon-related side effects as well as low efficacy against HCV infection. There is a need for the development of antiviral drugs that are effective in the treatment of HCV infection due to the low tolerance and disappointing efficacy of current therapies.

In a patient population where most of the patients are chronically infected and also where the asymptomatic and prognosis are unknown, effective medications should have significantly lower side effects than currently available treatments. Hepatitis C non-structural protein-3 (NS3) is a viral polyprotein and protease required for viral replication. In spite of the large number of viral variants associated with HCV infection, the active portion of NS3 proteinase is largely conserved to inhibit the fascinating aspect of interference. Recent success in the treatment of HIV with protease inhibitors supports the notion that the inhibition of NS3 is an important target in the battle against HCV.

HCV is a Flaviviridae type RNA virus. The HCV genome is enclosed and contains a single stranded RNA molecule composed of a Sirka 9600 base pair. It encodes a polypeptide consisting of about 3010 amino acids.

HCV multifunctional proteins are processed into ten separate polypeptides that perform a variety of functions by viral and host proteases. There are three structural proteins, C, E1 and E2. P7 protein has an unknown action and is composed of highly variable sequences. There are six non-structural proteins. NS3 includes two catalysis (isolated from association with NS2): serine protease at the N-terminus, and ATP-ase dependent helicase at the carboxy terminus, which requires NS4A as official. NS4A is tightly bound but is a non-covalent recognizer of serine protease.

NS3.4A proteinase is involved in cleaving four sites for viral polyproteins. NS3-NS4A cleavage is a self catalysis that occurs in cis form. The other three hydrolases, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B, all occur in the trans form. NS3 is a serine proteinase that is structurally classified as chymotrypsin-like proteinase. NS serine protease has proteolytic activity in itself, while HCV protease is not an effective enzyme in terms of catalyzed polyprotein cleavage. The central hydrophobic region of the NS4A protein has been shown to be necessary for this improvement. Complex formation of NS3A protein with NS4A appears to be necessary for the treatment step while enhancing proteolytic efficacy at all sites.

A general strategy for the development of antiviral drugs is to inactivate the enzyme encoded in the virus, including NS3, which is essential for the replication of the virus. Current attempts to develop NS3 proteinase inhibitors include S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics; Current Status and Emerging Strategies, Nature Rev. Drug Dicov. , 1, 867-881 (2002). More related patents describing the synthesis of HCV proteinase inhibitors are described in WO 00/59929 (2000); WO 99/07733 (1999); WO 00/09543 (2000); WO 99/50230 (1999); US 5851297 (1999).

The present invention relates to a novel macrocyclic compound and a method for treating a hepatitis C infection in a subject in need of treatment with said macrocyclic compound. The invention further relates to pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable salt, ester or prodrug thereof in combination with a pharmaceutically acceptable carrier or excipient.

A compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[Formula I]

Figure 112005043726247-pct00001

Where

A is H,-(C = O) -R 2 ,-(C = O) -OR 1 , -C (= O) -NH-R 2 , -C (= S) -NH-R 2 , -S (O) 2 -R 2 ,-(C = NR 1 ) -R 1 and-(C = NR 1 ) -NH-R 1 ;

G is -OH, -O- (C 1 -C 12 alkyl), -NHS (O) 2 -R 1 -, - (C = O) -R 1, - (C = O) -R 2, -C (= 0) -OR 1 , -C (C = 0) -OR 1 , and-(C = 0) -NH-R 1 ;

L is -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S (O) CH 2 CH 2- , -O-, -OCH 2- , -OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2- , -CF 2 CH 2- , and -CR x = CR x- (wherein R x = H or halogen);

j is 0, 1, 2, 3, or 4;

m is 0, 1, or 2;

s is 0, 1 or 2;

R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

R 2 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl , Substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

R 3 and R 4 are each independently selected from the group consisting of hydrogen, OH, CH 3 , CN, SH, halogen, NO 2 , NH 2 , amide, methoxy, trifluoromethoxy, and trifluoromethyl;

E represents a single bond or a double bond between two carbon atoms attached thereto; Also

W is a substituted or unsubstituted heterocyclic ring system.

In one embodiment of the present invention, E represents a double bond which results in the formation of the formula (II) or a pharmaceutically acceptable salt, ester, or prodrug thereof.

 [Formula II]

Figure 112005043726247-pct00002

Wherein the remaining substituents are as described above.

In one embodiment of the invention, E represents a single bond which results in the formation of the formula (III) or a pharmaceutically acceptable salt, ester, or prodrug thereof.

[Formula III]

Figure 112005043726247-pct00003

Wherein the remaining substituents are as described above.

In one embodiment of the invention, compounds represented by formulas (II) and (III), or pharmaceutically acceptable salts, esters, or prodrugs thereof, are described; here

W is

Figure 112005043726247-pct00004
,
Figure 112005043726247-pct00005
,
Figure 112005043726247-pct00006
And
Figure 112005043726247-pct00007
Is selected from the group consisting of

Q is a group consisting of absent, -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- Is selected from;

Q 'is selected from the group consisting of absent, -CH 2 -and -NH-;

Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero It is selected from the group consisting of cycloalkyl.

All other substituents are as defined above.

In one embodiment of the invention, compounds represented by formulas (II) and (III), or pharmaceutically acceptable salts, esters, or prodrugs thereof, are described; here

W is

Figure 112005043726247-pct00008
or
Figure 112005043726247-pct00009
It is selected from the group consisting of;

X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl.

All other substituents are as defined above.

In one embodiment of the invention, compounds represented by formulas (II) and (III), or pharmaceutically acceptable salts, esters, or prodrugs thereof, are described; here

W is

Figure 112005043726247-pct00010
Is; Also

X, Y and Z are independently H, N 3 , halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, C 1 -C 6 alkynyl, substituted alkynyl, Aryl, substituted aryl, -S-aryl, -S-substituted aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl, diarylamino, diheteroarylamino, aryl Alkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl, -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl, -NH-substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y or Y and Z are taken together with the carbon atoms to which they are attached to form an aryl, substituted aryl, heteroaryl and substituted heteroaryl cyclic moiety.

Another aspect of the invention is a compound according to any one of formulas, wherein W is substituted with one or more substituents; Each of said substituents is independently selected from any of the following (a), (b), (c), (d) or (e):

(a) alkenyl; Alkoxy; Alkoxyalkyl; Alkyl; Alkylamino; Alkylaryl; Alkylsulfonyl; Alkynyl; amides; Amido optionally mono-substituted with C 1 -C 6 alkyl; Aryl; Arylalkanoylalkyl; Arylalkyl; Arylaminoalkyl; Aryloxyalkyl; Arylsulfonyl; Cycloalkoxy; Cycloalkyl; Dialkylamino; Dialkylaminoalkyl; Diarylaminoalkyl; Haloalkyl; Heteroaryl; Heteroarylalkyl; Heterocyclo; Heterocycloalkyl; Heterocycloalkylalkyl; Thioalkyl; Monoalkylaminoalkyl; Sulfonyl; (Lower alkyl) sulfonyl; Haloalkyl; Carbosyl; amides; (Lower alkyl) amides; Heterocyclo optionally substituted with C 1 -C 6 alkyl; Perhaloalkyl; Sulfonyl; Thioalkyl; Urea, C (═O) —R 11 ; OC (= 0) R 11 ; C (= 0) OR 11 ; C (= 0) N (R 11 ) 2 ; C (= S) N (R 11 ) 2 ; SO 2 R 11 ; NHS (O 2 ) R 11 ; N (R 12 ) 2 ; N (R 12 ) C (= 0) R 11 ;

delete

Wherein each of said substituents may be optionally substituted up to three groups selected from halogen, OH, alkoxy, perhaloalkyl;

(b) C 7 -C 14 aralkyl; C 2 -C 7 cycloalkyl; C 6 -C 10 aryl; Heterocyclo; (Lower alkyl) -heterocyclo;

Wherein each aralkyl, cycloalkyl, aryl, heterocyclo or (lower alkyl) -heterocyclo may be optionally substituted with R 6 ;

Wherein R 6 is halogen, C 1 -C 6 alkyl; C 3 -C 6 cycloalkyl; C 1 -C 6 alkoxy; C 3 -C 6 cycloalkoxy; NO 2 ; N (R 7 ) 2 alkyl; NH-C (O) -R 7 or NH-C (O) -NHR 7 ; Wherein R 7 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;

Or R 6 is NH-C (O) -OR 8 , wherein R 8 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;

(c) N (R 5 ) 2 , NH-C (O) -R 5 , or NH-C (O) -NH-R 5 , wherein R 5 is independently H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, C 6 or C 10 aryl, C 7 -C 14 aralkyl, heterocyclo or (lower alkyl) -heterocyclo);

(d) NH-C (O) -OR 8 , wherein R 8 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;

(e) formyl; halogen; Hydroxy; NO 2 ; OH; SH; Halo; CN;

here

Each R 11 is independently H, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl , Heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, where their May be optionally substituted with up to 3 groups selected from halogen, OH, alkoxy and perhaloalkyl; Also

Each R 12 is independently H, formyl, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, hetero Arylalkyl, heteroaryl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, or diarylaminoalkyl, wherein any of these are halogen, OH, And optionally up to 3 groups selected from alkoxy and perhaloalkyl.

delete

 There is provided a compound of any one of the formulas wherein W is selected from the group consisting of the following substituents (a) and (b):

(a) an aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having up to 4 ring heteroatoms and 5 to 16 ring atoms selected from O, N and S, wherein the ring system is OH Optionally substituted with up to 3 ring substituents selected from the group consisting of CN, halogen, formyl, R 10 and R 11 ;

(b) an aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having up to 4 ring heteroatoms and 5 to 16 ring atoms selected from O, N and S, wherein the ring system is OH Optionally substituted with up to three ring substituents selected from the group consisting of CN, halogen, formyl, and R 10 ;

here,

Each R 10 is independently alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl , Arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, heteroaryl or urea, wherein these One is halogen, OH, alkoxy and perhaloalkyl; C (= 0) -R 11 ; OC (= 0) R 11 ; C (= 0) OR 11 ; C (= 0) N (R 11 ) 2 ; C (= S) N (R 11 ) 2 ; SO 2 R 11 ; NHS (O 2 ) R 11 ; N (R 12 ) 2 ; And N (R 12 ) C (= 0) R 11 optionally substituted with up to 3 groups;

Each R 11 is independently H, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl , Heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, wherein any of these May be optionally substituted with up to 3 groups selected from halogen, OH, alkoxy and perhaloalkyl;

delete

Each R 12 is independently H, formyl, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, hetero Arylalkyl, heteroaryl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, or diarylaminoalkyl, wherein any of these are halogen, OH, And optionally up to 3 groups selected from alkoxy and perhaloalkyl.

delete

W is an aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having up to 4 ring heteroatoms and 5 to 16 ring atoms selected from O, N and S, wherein the ring system is OH , CN, halogen, formyl, a compound of any one of the formulas optionally substituted with up to three ring substituents selected from the group consisting of R 10 and R 11 .

W is an aliphatic heteromonocyclic ring system having up to 4 ring heteroatoms and 5 to 7 ring atoms selected from O, N and S, wherein the ring system is OH, CN, halogen, formyl, R 10 And at least three ring substituents selected from the group consisting of R 11 .

 The compound of any one of formulas wherein said optionally substituted aliphatic heteromonocyclic ring system has one or two ring heteroatoms and five ring atoms selected from O, N and S.

 The optionally substituted aliphatic heteromonocyclic ring system may be selected from the group consisting of pyrrolidine, pyrazolidine, pyrroline, tetrahydrothiophene, dihydrothiophene, tetrahydrofuran, dihydrofuran, imidazoline, tetrahydroimidazole, A compound of any one of the formulas selected from the group consisting of dihydropyrazole, tetrahydropyrazole and oxazoline.

 The compound of any one of formulas wherein said optionally substituted aliphatic heteromonocyclic ring system has one or two ring heteroatoms and six ring atoms selected from O, N and S.

Said optionally substituted aliphatic heteromonocyclic ring system comprising pyridine, piperidine, dihydropyridine, tetrahydropyridine, dihydropyran, tetrahydropyran, dioxane, piperazine, dihydropyrimidine, tetrahydropyrimidine, A compound of any one of the formulas selected from the group consisting of perhydro pyrimidine, morpholine, thioxane and thiomorpholine.

 And wherein said optionally substituted aliphatic heteromonocyclic ring system has one or two ring heteroatoms and seven ring atoms selected from O, N and S.

 And wherein said optionally substituted aliphatic heteromonocyclic ring system is selected from the group consisting of hexamethyleneimine and hexamethylene sulfide.

W is an aliphatic heterobicyclic ring system having up to 4 ring heteroatoms and 5 to 16 ring atoms selected from O, N and S, wherein the ring system is OH, CN, halogen, formyl, and R A compound of any of formulas optionally substituted with up to 3 ring substituents selected from the group consisting of 10 .

 The compound of any one of formulas wherein said optionally substituted aliphatic heterocyclic ring system has 1 to 4 ring heteroatoms and 8 to 12 ring atoms selected from O, N and S.

 Wherein said optionally substituted aliphatic heterobicyclic ring system has one or two ring heteroatoms selected from O and N and 8 to 12 ring atoms.

W is an aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having up to 4 ring heteroatoms and 5 to 16 ring atoms selected from O, N and S, wherein the ring system is OH , CN, halogen, formyl, and any one of formulas optionally substituted with up to three ring substituents selected from the group consisting of R 10 .

W is an aromatic heteromonocyclic ring system having up to 4 ring heteroatoms and 5 to 7 ring atoms selected from O, N and S, wherein the ring system is OH, CN, halogen, formyl and R 10 A compound of any one of the formulas optionally substituted with up to 3 ring substituents selected from the group consisting of:

 And wherein said optionally substituted aromatic heteromonocyclic ring system has one or two ring heteroatoms and five ring atoms selected from O, N and S.

 The optionally substituted aromatic heteromonocyclic ring system consists of pyrrole, pyrazole, porphyrin, furan, thiophene, imidazole, oxazole, oxadiazole, isoxazole, thiazole, thiadiazole, and isothiazole. A compound of any one of the formulas selected from the group.

 And wherein said optionally substituted aromatic heteromonocyclic ring system has one, two or three ring heteroatoms and six ring atoms selected from O, N and S.

 And wherein said optionally substituted aromatic heteromonocyclic ring system is selected from the group consisting of pyridine, pyrimidine, pyrazine, pyran and triazine.

 And wherein said optionally substituted aromatic heteromonocyclic ring system has 3 or 4 ring heteroatoms and 5 ring atoms selected from O, N and S.

 The compound of any one of formulas wherein the optionally substituted aromatic heteromonocyclic ring system is triazolyl or tetrazolyl.

W is an aromatic heterobicyclic ring system having up to 4 ring heteroatoms and 8 to 12 ring atoms selected from O, N and S, wherein the ring system is OH, CN, halogen, formyl and R 10 A compound of any one of the formulas optionally substituted with up to 3 ring substituents selected from the group consisting of:

 The optionally substituted aromatic heterobicyclic ring system includes adenine, azabenzimidazole, azaindole, benzimidazole, benzoisothiazole, benzofuran, benzoisoxazole, benzoxazole, benzothiadiazole and benzothiazole. , Benzothiene, benzothiophene, carbazole, cinnoline, guanine, imidazopyridine, indazole, indole, isoindole, isoquinoline, phthalazine, purine, pyrrolopyridine, quinazoline, quinoline, quinoxaline, thianaph A compound of any one of the formulas selected from the group consisting of ten and xanthine.

W is an aromatic heterotricyclic ring system having up to 4 ring heteroatoms and 10 to 12 ring atoms selected from O, N and S, wherein the ring system is OH, CN, halogen, formyl, R 10 And at most 3 ring substituents selected from the group consisting of R 11 .

 The optionally substituted aromatic heterotricyclic ring system of any one of formulas selected from the group consisting of carbazole, bizenzofuran, psoraren, dibenzothiophene, phenazine, thianthrene, phenanthroline, phenanthridine compound.

Another embodiment is a compound of Formula (II).

[Formula II]

Figure 112005043726247-pct00011

Where

A is H,-(C = O) -R 2 ,-(C = O) -OR 1 , -C (= O) -NH-R 1 , -C (= 0) -NH-R 2 , -C (= S) -NH-R 2, -, -S (O) 2 -R 2 ,-(C = NR 1 ) -R 1 and-(C = NR 1 ) -NH-R 1 Become;

G is —OH, —O— (C 1 -C 12 alkyl), —NHS (O) 2 —R 1 —, — (C═O) —R 2 , —C (═O) —OR 1 , and — (C═O) —NH—R 2 is selected from the group consisting of;

L is absent, -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S (O) CH 2 CH 2- , -O-, -OCH 2- , -OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2- , -CF 2 CH 2 -and -CR x = CR x- (wherein R x = H or halogen);

W is

Figure 112005043726247-pct00012
,
Figure 112005043726247-pct00013
,
Figure 112005043726247-pct00014
And
Figure 112005043726247-pct00015
Is selected from the group consisting of

Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ;

Q 'is selected from the group consisting of absent, -CH 2 -and -NH-;

Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl;

j is 0, 1, 2, 3, or 4;

m is 0, 1, or 2;

s is 0, 1 or 2;

R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

R 2 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, Arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl.

A is-(C = O) -OR 1 ;

G is hydroxyl;

L is absent;

j is 3; m = s = 1, also

A compound of formula (II) wherein R 3 and R 4 are hydrogen.

  A is-(C = O) -O-tert-butyl;

G is hydroxyl;

L is absent;

j is 3;

m = s = 1, also

A compound of formula (II) wherein R 3 and R 4 are hydrogen.

A is-(C = O) -OR 1 ;

G is hydroxyl;

L is absent;

W

Figure 112005043726247-pct00016
Is;

j is 3;

m = s = 1, also

R 3 and R 4 are hydrogen.

A is-(C = O) -O-tert-butyl;

G is hydroxyl;

L is absent;

W

Figure 112005043726247-pct00017
,

j is 3; m = s = 1, also

A compound of formula (II) wherein R 3 and R 4 are hydrogen.

Another embodiment is a compound of Formula III:

[Formula III]

Figure 112005043726247-pct00018

Where

A is H,-(C = O) -R 2 ,-(C = O) -OR 1 , -C (= O) -NH-R 2 , -C (= S) -NH-R 2 , -S (O) 2 -R 2 ,-(C = NR 1 ) -R 1 and-(C = NR 1 ) -NH-R 1 ;

G is —OH, —O— (C 1 -C 12 alkyl), —NHS (O) 2 —R 1 , — (C═O) —R 2 , —C (═O) —OR 1 , and — ( C = O) -NH-R 2 ;

L is absent, -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S (O) CH 2 CH 2- , -O-, -OCH 2- , -OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2- , -CF 2 CH 2 -and -CR x = CR x- (wherein R x = H or halogen);

W is

Figure 112005043726247-pct00019
,
Figure 112005043726247-pct00020
,
Figure 112005043726247-pct00021
And
Figure 112005043726247-pct00022
Is selected from the group consisting of

Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ;

Q 'is selected from the group consisting of absent, -CH 2 -and -NH-;

Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl;

j is 0, 1, 2, 3, or 4;

m is 0, 1, or 2;

s is 0, 1 or 2;

R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

R 2 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, Arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl.

A is-(C = O) -OR 1 ;

G is hydroxyl;

L is absent;

j is 3;

m = s = 1, also

A compound according to formula (III), wherein R 3 and R 4 are hydrogen.

 A is-(C = O) -O-tert-butyl;

G is hydroxyl;

L is absent;

j is 3;

m = s = 1, also

A compound according to formula (III), wherein R 3 and R 4 are hydrogen.

A is-(C = O) -OR 1 ;

G is hydroxyl;

L is absent;

W

Figure 112005043726247-pct00023
,

j is 3;

m = s = 1, also

A compound according to formula (III), wherein R 3 and R 4 are hydrogen.

A is-(C = O) -O-tert-butyl;

G is hydroxyl;

L is absent;

W

Figure 112005043726247-pct00024
,

j is 3;

m = s = 1, also

A compound according to formula (III), wherein R 3 and R 4 are hydrogen.

A compound of formula (II)

[Formula II]

Figure 112005043726247-pct00025

Where

A is H,-(C = O) -R 2 ,-(C = O) -OR 1 , -C (= O) -NH-R 2 , -C (= S) -NH-R 2 , -S (O) 2 -R 2 ,-(C = NR 1 ) -R 1 and-(C = NR 1 ) -NH-R 1 ;

G is —OH, —O— (C 1 -C 12 alkyl), —NHS (O) 2 —R 1 , — (C═O) —R 2 , —C (═O) —OR 1 , and — ( C = O) -NH-R 2 ;

L is absent, -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S (O) CH 2 CH 2- , -O-, -OCH 2- , -OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2- , -CF 2 CH 2 -and -CR x = CR x- (wherein R x = H or halogen);

W is

Figure 112006092596674-pct00026
And
Figure 112006092596674-pct00027
Is selected from the group consisting of

Wherein X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 -alkylamino, -CH 2 -dialkylamino, -CH 2 -arylamino, -CH 2 -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, Substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;

 j is 0, 1, 2, 3, or 4;

m is 0, 1, or 2;

s is 0, 1 or 2;

R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

R 2 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, Arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl.

A is-(C = O) -OR 1 ;

G is hydroxyl;

L is absent;

j is 3;

m = s = 1, also

A compound according to formula (II), wherein R 3 and R 4 are hydrogen.

 A is-(C = O) -O-tert-butyl;

G is hydroxyl;

L is absent;

j is 3;

m = s = 1, also

A compound according to formula (II), wherein R 3 and R 4 are hydrogen.

A is-(C = O) -OR 1 ;

G is hydroxyl;

L is absent;

W

Figure 112005043726247-pct00028
,

j is 3;

m = s = 1, also

A compound according to formula (II), wherein R 3 and R 4 are hydrogen.

 A is-(C = O) -O-tert-butyl;

G is hydroxyl;

L is absent;

W

Figure 112005043726247-pct00029
,

j is 3;

m = s = 1, also

A compound according to formula (III), wherein R 3 and R 4 are hydrogen.

Another embodiment is a compound of Formula III:

[Formula III]

Figure 112005043726247-pct00030

Where

A is H,-(C = O) -R 2 ,-(C = O) -OR 1 , -C (= O) -NH-R 2 , -C (= S) -NH-R 2 , -S (O) 2 -R 2 ,-(C = NR 1 ) -R 1 and-(C = NR 1 ) -NH-R 1 ;

G is —OH, —O— (C 1 -C 12 alkyl), —NHS (O) 2 —R 1 , — (C═O) —R 2 , —C (═O) —OR 1 , and — ( C = O) -NH-R 2 ;

L is absent, -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -O-, -OCH 2 -, -OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2- , -CF 2 CH 2- , and -CR x = CR x- ( Wherein R x = H or halogen);

W is

Figure 112007053853814-pct01026
And
Figure 112007053853814-pct01027
And X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 -alkylamino, -CH 2 -dialkylamino, -CH 2 -arylamino, -CH 2 -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -Diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroallylalkyl, substituted heteroarylalkyl, heterocycloalkyl; And substituted heterocycloalkyl; Or X and Y are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to which they are attached to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;

 j is 0, 1, 2, 3, or 4;

m is 0, 1, or 2;

s is 0, 1 or 2;

R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

R 2 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, Arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl.

A is-(C = O) -OR 1 ;

G is hydroxyl;

L is absent;

j is 3;

m = s = 1, also

A compound according to formula (III), wherein R 3 and R 4 are hydrogen.

 A is-(C = O) -O-tert-butyl;

G is hydroxyl;

L is absent

j is 3;

m = s = 1, also

A compound according to formula (III), wherein R 3 and R 4 are hydrogen.

A is-(C = O) -OR 1 ;

G is hydroxyl;

L is absent;

W

Figure 112005043726247-pct00033
,

j is 3;

m = s = 1, also

A compound according to formula (III), wherein R 3 and R 4 are hydrogen.

 A is-(C = O) -O-tert-butyl;

G is hydroxyl;

L is absent;

W

Figure 112005043726247-pct00034
,

j is 3;

m = s = 1, also

A compound according to formula (III), wherein R 3 and R 4 are hydrogen.

 A compound of formula (IV)

[Formula IV]

Figure 112005043726247-pct00035

Where

A is hydrogen,-(C = O) -R 1 ,-(C = O) -OR 1 , -C (= O) -NH-R 2 , -C (= S) -NH-R 2 , -S (O) 2 -R 2 ,-(C = NR 1 ) -R 1 or-(C = NR 1 ) -NH-R 1 ;

G is -OH, -O- (C 1 -C 12 alkyl), -NHS (O) 2 -R 1, - (C = O) -R 2, -C (= O) -OR 1, or - ( C═O) —NH—R 2 ;

L is -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S (O) CH 2 CH 2- , -O-, -OCH 2 --OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2- , -CF 2 CH 2 -or -CR x = CR x- , wherein R x = H or halogen;

X, Y and Z are independently hydrogen, N 3 , halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, C 1 -C 6 alkynyl, substituted alkynyl, Aryl, substituted aryl, -S-aryl, -S-substituted aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl, diarylamino, diheteroarylamino, aryl Alkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl, -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl,- NH-substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

Or X and Y or Y and Z are taken together with the carbon atom to which they are attached to form an aryl, substituted aryl, heteroaryl or substituted heteroadyl cyclic moiety;

 j is 0, 1, 2, 3, or 4;

m is 0, 1, or 2;

s is 0, 1 or 2;

R 1 is hydrogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl;

R 2 is hydrogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, Arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl;

R 3 and R 4 are each independently hydrogen and methyl.

A is-(C = O) -OR 1 ;

G is hydroxyl;

L is absent;

j is 3;

m = s = 1, also

A compound according to formula (IV), wherein R 3 and R 4 are hydrogen.

 A is-(C = O) -O-tert-butyl;

G is hydroxyl;

L is absent

j is 3;

m = s = 1, also

A compound according to formula (IV), wherein R 3 and R 4 are hydrogen.

A compound of formula (V)

Formula (V)

Figure 112005043726247-pct00036

Where

A is hydrogen,-(C = O) -R 1 ,-(C = O) -OR 1 , -C (= O) -NH-R 2 , -C (= S) -NH-R 2 , -S (O) 2 -R 2 ,-(C = NR 1 ) -R 1 or-(C = NR 1 ) -NH-R 1 ;

G is -OH, -O- (C 1 -C 12 alkyl), -NHS (O) 2 -R 1, - (C = O) -R 2, -C (= O) -OR 1, or - ( C═O) —NH—R 2 ;

L is absent, -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S ( O) CH 2 CH 2- , -O-, -OCH 2 --OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2 -,- CF 2 CH 2 -or -CR x = CR x- , wherein R x = H or halogen;

X, Y and Z are independently hydrogen, N 3 , halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, C 1 -C 6 alkynyl, substituted alkynyl, Aryl, substituted aryl, -S-aryl, -S-substituted aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl, diarylamino, diheteroarylamino, aryl Alkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl, -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl,- NH-substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

Or X and Y or Y and Z are taken together with the carbon atom to which they are attached to form an aryl, substituted aryl, heteroaryl or substituted heteroadyl cyclic moiety;

 j is 0, 1, 2, 3, or 4;

m is 0, 1, or 2;

s is 0, 1 or 2;

R 1 is hydrogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl;

R 2 is hydrogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, Arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl;

R 3 and R 4 are each independently hydrogen and methyl.

A is-(C = O) -OR 1 ;

G is hydroxyl;

L is absent;

j is 3;

m = s = 1, also

A compound according to formula (V), wherein R 3 and R 4 are hydrogen.

 A is-(C = O) -O-tert-butyl;

G is hydroxyl;

L is absent

j is 3;

m = s = 1, also

A compound according to formula (V), wherein R 3 and R 4 are hydrogen.

Another embodiment is a compound of Formula (II) or (III) as described herein:

A is H,-(C = O) -R 2 ,-(C = O) -OR 1 , -C (= O) -NH-R 1 , -C (= O) -NH-R 2 , -C (= S) -NH-R 2, -, and -S (O) 2 -R 2 ; G is -OH, -O- (C 1 -C 12 alkyl), -NHS (O) 2 -R 1 -, - (C = O) -R 1, -C (= O) -OR 1, and - Is selected from the group consisting of (C═O) —NH—R 1 ; L is absent, -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S (O) CH 2 CH 2- , -O-, -OCH 2- , -OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2- , and -CF 2 CH 2- ; W

Figure 112005043726247-pct00037
,
Figure 112005043726247-pct00038
,
Figure 112005043726247-pct00039
And
Figure 112005043726247-pct00040
Q is absent, -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O) -Is selected from the group consisting of; Q 'is absent, is selected from the group consisting of -CH 2 -and -NH-; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j is 0, 1, 2, 3, or 4; m is 0, 1, or 2; s is 0, 1 or 2; R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; R 2 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl , Substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; And compounds of formula (II) or (III), wherein R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl and L is absent; W is

Figure 112005043726247-pct00041
,
Figure 112005043726247-pct00042
,
Figure 112005043726247-pct00043
And
Figure 112005043726247-pct00044
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Q 'is absent, is selected from the group consisting of -CH 2 -and -NH-; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; a compound of formula (II) wherein m = s = 1 and R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl; G is hydroxyl and L is absent; W

Figure 112005043726247-pct00045
,
Figure 112005043726247-pct00046
,
Figure 112005043726247-pct00047
And
Figure 112005043726247-pct00048
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Q 'is absent, is selected from the group consisting of -CH 2 -and -NH-; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; a compound of formula (II) wherein m = s = 1 and R 3 and R 4 are hydrogen;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl and L is absent; W

Figure 112005043726247-pct00049
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; a compound of formula (II) wherein m = s = 1 and R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl; G is hydroxyl and L is absent; W

Figure 112005043726247-pct00050
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; a compound of formula (II) wherein m = s = 1 and R 3 and R 4 are hydrogen;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl and L is absent; W is

Figure 112005043726247-pct00051
,
Figure 112005043726247-pct00052
,
Figure 112005043726247-pct00053
And
Figure 112005043726247-pct00054
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Q 'is absent, is selected from the group consisting of -CH 2- , -O-, and -NH-; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; a compound of formula (III) wherein m = s = 1 and R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl, G is hydroxyl and L is absent; W is

Figure 112005043726247-pct00055
,
Figure 112005043726247-pct00056
,
Figure 112005043726247-pct00057
And
Figure 112005043726247-pct00058
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Q 'is absent, is selected from the group consisting of -CH 2 -and -NH-; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; a compound of formula (III) wherein m = s = 1 and R 3 and R 4 are hydrogen;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl and L is absent; W is

Figure 112005043726247-pct00059
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; a compound of formula (III) wherein m = s = 1 and R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl, G is hydroxyl and L is absent; W is

Figure 112005043726247-pct00060
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; m = s = 1, and R 3 and R 4 are hydrogen.

Other embodiments are as follows:

A is H,-(C = O) -R 2 ,-(C = O) -OR 1 , -C (= O) -NH-R 2 , -C (= S) -NH-R 2 and -S (O) 2 -R 2 ; G is -OH, -O- (C 1 -C 12 alkyl), -NHS (O) 2 -R 1, - (C = O) -R 2, -C (= O) -OR 1, and - ( C = O) -NH-R 2 ; L is absent, -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S (O) CH 2 CH 2- , -O-, -OCH 2- , -OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2 -and -CF 2 CH 2- ; W

Figure 112007053853814-pct00061
And
Figure 112007053853814-pct00062
Is selected from the group consisting of

Wherein X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 -alkylamino, -CH 2 -dialkylamino, -CH 2 -arylamino, -CH 2 -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, Substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y, to which they are attached, are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 0, 1, 2, 3, or 4; m = 0, 1, or 2; s = 0, 1 or 2; R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; R 2 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl , Substituted heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; A compound of formula (II) or (III), wherein R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent, W is

Figure 112007053853814-pct00063
And
Figure 112007053853814-pct00064
It is selected from the group consisting of; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y, to which they are attached, are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; A compound of formula (II) wherein R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent; W

Figure 112005043726247-pct00065
or
Figure 112005043726247-pct00066
It is selected from the group consisting of; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y, to which they are attached, are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; A compound of formula (II) wherein R 3 and R 4 are hydrogen;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent; W

Figure 112005043726247-pct00067
Is; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y, to which they are attached, are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; A compound of formula (II) wherein R 3 and R 4 are hydrogen.

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent; W

Figure 112005043726247-pct00068
Is; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y, to which they are attached, are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; A compound of formula (II) wherein R 3 and R 4 are hydrogen;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent; W

Figure 112007053853814-pct00069
And
Figure 112007053853814-pct00070
It is selected from the group consisting of; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y, to which they are attached, are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; A compound of formula (III) wherein R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent; W

Figure 112005043726247-pct00071
or
Figure 112005043726247-pct00072
It is selected from the group consisting of; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y, to which they are attached, are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; A compound of formula (III) wherein R 3 and R 4 are hydrogen;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent; W

Figure 112005043726247-pct00073
Is; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y, to which they are attached, are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; A compound of formula (III) wherein R 3 and R 4 are hydrogen.

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent; W

Figure 112005043726247-pct00074
Is; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y, to which they are attached, are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; A compound of formula (III) wherein R 3 and R 4 are hydrogen;

 Another embodiment is a compound of Formula (IV) or (V).

[Formula IV] [Formula V]

Figure 112005043726247-pct00075
Figure 112005043726247-pct00076

Where

A is H,-(C = O) -R 2 ,-(C = O) -OR 1 , -C (= O) -NH-R 2 , -C (= S) -NH-R 2 , or- S (O) 2 -R 2 ; G is -OH, -O- (C 1 -C 12 alkyl), -NHS (O) 2 -R 1, - (C = O) -R 2, -C (= O) -OR 1, or - ( C═O) —NH—R 2 ; L is absent, -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S ( O) CH 2 CH 2- , -O-, -OCH 2 --OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2- , or -CF 2 CH 2- ; X, Y and Z are independently H, N 3 , halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, C 1 -C 6 alkynyl, substituted alkynyl, Aryl, substituted aryl, -S-aryl, -S-substituted aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl, diarylamino, diheteroarylamino, aryl Alkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl, -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl,- NH-substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y or Y and Z are taken together with the carbon atom to which they are attached to form an aryl, substituted aryl, heteroaryl or substituted heteroadyl cyclic moiety; j is 0, 1, 2, 3, or 4; m is 0, 1, or 2; s is 0, 1 or 2; R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl; R 2 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, Arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl; R 3 and R 4 are each independently hydrogen and methyl.

A is-(C = O) -OR 1 ; G is hydroxyl; L is absent; j is 3; m = s = 1, and R 3 and R 4 are hydrogen.

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent; j is 3; m = s = 1, and R 3 and R 4 are hydrogen.

A is-(C = O) -OR 1 ; G is hydroxyl; L is absent; j is 3; m = s = 1, and R 3 and R 4 are hydrogen.

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent; j is 3; m = s = 1, and R 3 and R 4 are hydrogen.

Another embodiment is that W

Figure 112007053853814-pct00077
Where V, X, Y and Z are each independently

a) 0, 1, 2 or selected from O, S or N optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl -C 1 -C 6 alkyl containing 3 heteroatoms;

b) 0, 1, 2 or selected from O, S or N optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; -C 2 -C 6 alkenyl containing 3 heteroatoms;

c) 0, 1, 2 or selected from O, S or N optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl -C 2 -C 6 alkynyl containing 3 heteroatoms;

d) aryl;

e) substituted aryl;

f) heteroaryl;

g) substituted heteroaryl;

h) heterocycloalkyl; or

i) selected from substituted heterocycloalkyl;

Or a cyclic moiety selected from V and X, X and Y, or Y and Z taken together with the carbon atom to which they are attached, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl To a compound of formula (I).

Another real sun is W

Figure 112007053853814-pct00078
Where X, Y and Z are each independently

a) 0, 1, 2 or selected from O, S or N optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl -C 1 -C 6 alkyl containing 3 heteroatoms;

b) 0, 1, 2 or selected from O, S or N optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; -C 2 -C 6 alkenyl containing 3 heteroatoms;

c) 0, 1, 2 or selected from O, S or N optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl -C 2 -C 6 alkynyl containing 3 heteroatoms;

d) aryl;

e) substituted aryl;

f) heteroaryl;

g) substituted heteroaryl;

h) heterocycloalkyl; or

i) selected from substituted heterocycloalkyl;

Or Y and Z are taken together with the carbon atom to which they are attached to form a cyclic moiety selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl.

The remaining substituents are all listed above.

 Another embodiment includes the steps of (i) reacting a proline derivative of formula (VI) with a nucleophilic heterocyclic compound and (ii) converting the obtained compound to a compound of formula (I) as described herein It is a method for producing a compound of formula (I). [Formula VI]

Figure 112005043726247-pct00079

Where

P is a nitrogen-protecting group (eg BOC);

L is a leaving group (eg halides, OMs);

      R is optionally substituted alkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl.

Another embodiment relates to (i) reacting a compound of formula (VII) with a nucleophilic heterocyclic compound; (ii) a process for the preparation of the compound of formula (I) which comprises converting the obtained compound into the compound of formula (I) described herein.

[Formula VII]

Figure 112005043726247-pct00080

Where

L is a leaving group (eg halides, OMs);

A is a nitrogen protecting group (eg BOC);

       The remaining variants are as defined in formula (I).

In another embodiment, the present invention provides a process for reacting a (i) proline derivative (including one having a mesylate substituent) described herein with a nucleophilic form of a heterocyclic compound (eg, a protonated or corresponding metal salt form), (ii) converting the obtained compound into a compound of any of the formulas described herein (e.g., in formulas (I) to (iii) having a substitutional variant defined herein) It relates to a method for preparing any one compound. In another aspect the method comprises one or more intermediate compounds described herein or comprises combining one or more steps or agents or modifications as described specifically in the Examples and Schemes herein.

In another aspect, the invention relates to a method of preparing a pharmaceutical composition comprising combining a compound of the formula described herein or a pharmaceutically acceptable salt, ester or prodrug thereof with a pharmaceutically acceptable carrier. It is about.

Another embodiment is a compound of Formula (VI) or (VII), wherein l is OMs and A and the remaining variants are as defined herein in any one of Formulas (eg, I, II, III).

A first embodiment of the invention is a compound represented by formula (I) above, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.

In some embodiments, the compound may be of the formula described herein (including certain substitutional variants as defined herein) selected from the following aromatics in which W may be optionally substituted.

Figure 112007053853814-pct00081
Figure 112007053853814-pct00082
Figure 112007053853814-pct00083
Figure 112007053853814-pct00084
Figure 112007053853814-pct00085
Figure 112007053853814-pct00086
Figure 112007053853814-pct00087

1H-pyrrole 1H-imidazole 1H-pyrazole furan thiophene oxazole thiazole

Figure 112007053853814-pct01038
Figure 112007053853814-pct00089
Figure 112007053853814-pct00090
Figure 112007053853814-pct00091
Figure 112007053853814-pct00092
Figure 112007053853814-pct00093
Figure 112007053853814-pct00094

Isoxazole isothiazole pyridine pyridazine pyrimidine pyrazine phthalazine

Figure 112007053853814-pct00095
Figure 112007053853814-pct00096
Figure 112007053853814-pct00097
Figure 112007053853814-pct00098
Figure 112007053853814-pct00099

Quinoxaline Quinazolin Quinoline Cinolin 1H-Pyrrolo- [2,3] pyridine

Figure 112005043726247-pct00100
Figure 112005043726247-pct00101
Figure 112005043726247-pct00102
Figure 112005043726247-pct00103
Figure 112005043726247-pct00104
Figure 112005043726247-pct00105

1H-indole 1H-benzoimidazole 1H-indazole 7H-purine benzothiazole benzoxazole

Figure 112007053853814-pct00106
Figure 112007053853814-pct00107
Figure 112007053853814-pct00108

1H-imidazo [4,5-c] pyridine 1H-imidazole [4,5-b] pyridine 1,3-dihydroxy-benzoimidazol-2-one

Figure 112007053853814-pct00109
Figure 112007053853814-pct00110
Figure 112007053853814-pct00111

1,3-dihydro-benzoimidazol-2-thione 2,3-dihydro-1H-indole 1,3-dihydro-indol-2-one

Figure 112007053853814-pct00112
Figure 112007053853814-pct00113
Figure 112007053853814-pct00114

1H-indole-2,3-dione 1,3-dihydro-benzoimidazol-2-one 1H-pyrrolo [2,3-c] pyridine

Figure 112007053853814-pct00115
Figure 112007053853814-pct00116
Figure 112007053853814-pct00117
Figure 112007053853814-pct00118

  Benzofuran benzo [b] thiophene benzo [d] isoxazole benzo [d] isothiazole

Figure 112007053853814-pct00119
Figure 112007053853814-pct00120
Figure 112007053853814-pct00121

1H-quinolin-2-ol 1H-quinolin-4-one 1H-quinazolin-4-one

Figure 112005043726247-pct00122
Figure 112005043726247-pct00123

9H-carbazole 1H-quinazolin-2-one

In other embodiments, the compound may be of the formula described herein (including certain substitutional variants as defined herein) selected from the following non-aromatics, where W may be optionally substituted.

Non-aromatic

Figure 112007053853814-pct00124
Figure 112007053853814-pct00125
Figure 112007053853814-pct00126
Figure 112007053853814-pct00127

Aziridine azetidine pyrrolidine 4,5-dihydro-1H-pyrazole

Figure 112007053853814-pct00128
Figure 112007053853814-pct00129
Figure 112007053853814-pct00130
Figure 112007053853814-pct00131

Pyrazolidine imidazolidin-2-one imidazolidine-2-thione pyrrolidin-2-one

Figure 112007053853814-pct00132
Figure 112007053853814-pct00133
Figure 112007053853814-pct00134
Figure 112007053853814-pct00135

Pyrrolidine-2,5-dione piperidine-2,6-dione piperidine-2-one piperazine-2,6-dione

Figure 112007053853814-pct00136
Figure 112007053853814-pct00137
Figure 112007053853814-pct00138
Figure 112007053853814-pct00139

Piperazine-2-one piperazine morpholine thiomorpholine 1,1-dioxide

Figure 112007053853814-pct00140
Figure 112007053853814-pct00141
Figure 112007053853814-pct00142
Figure 112007053853814-pct00143

Pyrazolidin-3-one imizazolidine-2,4-dione piperidine tetrahydro-furan

Figure 112007053853814-pct00144
Figure 112007053853814-pct00145
Figure 112007053853814-pct00146

Tetrahydro-pyran [1,4] dioxane 1,2,3,6-tetrahydro-pyridine

Another embodiment of the present invention is a compound represented by the above-described formula (II) wherein W is tetrazole or a derivative thereof, or a pharmaceutically acceptable salt, ester thereof, in combination with a pharmaceutically acceptable carrier or excipient. Or prodrugs.

Another embodiment of the present invention is a compound represented by the above-mentioned formula (III) wherein W is tetrazole or a derivative thereof, or a pharmaceutically acceptable salt, ester thereof, in combination with a pharmaceutically acceptable carrier or excipient. Or prodrugs.

Exemplary tetrazolyl macrocyclic compounds of the present invention and related methods are described in US Provisional Application Numbers, filed Feb. 13, 2003. (Changes of US 10 / 365,854). Representative classes of the invention include, but are not limited to, the following compounds.

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent, W is

Figure 112005043726247-pct00147
,
Figure 112005043726247-pct00148
,
Figure 112005043726247-pct00149
And
Figure 112005043726247-pct00150
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Q 'is absent, selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O) 2 -and-(C = O)- Become; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; m = s = 1; And R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent, W is

Figure 112005043726247-pct00151
,
Figure 112005043726247-pct00152
,
Figure 112005043726247-pct00153
And
Figure 112005043726247-pct00154
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Q 'is absent, is selected from the group consisting of -CH 2 -and -NH-; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; m = s = 1; Also compounds of formula (II) wherein R 3 and R 4 are hydrogen;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent, W is

Figure 112005043726247-pct00155
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; m = s = 1; Also compounds of formula (II) wherein R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent, W is

Figure 112005043726247-pct00156
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; m = s = 1; Also compounds of formula (II) wherein R 3 and R 4 are hydrogen;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent, W is

Figure 112005043726247-pct00157
,
Figure 112005043726247-pct00158
,
Figure 112005043726247-pct00159
And
Figure 112005043726247-pct00160
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Q 'is selected from the group consisting of absent, -CH 2- , and -NH-; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; m = s = 1; And R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent, W is

Figure 112005043726247-pct00161
,
Figure 112005043726247-pct00162
,
Figure 112005043726247-pct00163
And
Figure 112005043726247-pct00164
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Q 'is absent, is selected from the group consisting of -CH 2 -and -NH-; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; m = s = 1; Also compounds of formula (III) wherein R 3 and R 4 are hydrogen;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent, W is

Figure 112005043726247-pct00165
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; m = s = 1; Also compounds of formula (III) wherein R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent, W is

Figure 112005043726247-pct00166
Is; Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ; Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl; j = 3; m = s = 1; Also compounds of formula (III) wherein R 3 and R 4 are hydrogen;

Representative compounds of the invention include, but are not limited to, the following compounds.

Table 1 A G L W Q Y J R 3 , R 4 Compounds of formula (II); m = s = 3 tBOC OH Absent

Figure 112005043726247-pct00167
Absent Phenyl 3 R 3 = R 4 = H; tBOC OH Nonexistence
Figure 112005043726247-pct00168
Nonexistence 2-bromophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00169
Nonexistence 3-bromophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00170
Nonexistence 4-bromophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00171
Nonexistence 5-bromo-thienyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00172
Nonexistence 2-bromo-4-pyridyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00173
Nonexistence 2-biphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00174
Nonexistence 3-biphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00175
Nonexistence 4-biphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00176
Nonexistence 3- (3-thienyl) phenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00177
Nonexistence 3- (p-trifluoromethoxyphenyl) phenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00178
Nonexistence 3- (p-cyanophenyl) phenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00179
Nonexistence 4- (3-thienyl) phenyl 3 R 3 = R 4 = H;

Table 1 A G L W Q Y J R 3 , R 4 tBOC OH Nonexistence

Figure 112007053853814-pct00180
Nonexistence 4- (p-trifluoromethoxyphenyl) phenyl 3 R 3 = R 4 = H; tBOC OH Nonexistence
Figure 112007053853814-pct00181
Nonexistence 4- (p-cyanophenyl) phenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00182
Nonexistence 5-phenyl-2-thienyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00183
Nonexistence 5-phenyl-3-pyridyl 3 R 3 = R 4 = H;
tBOC OEt Nonexistence
Figure 112007053853814-pct00184
Nonexistence 3-chloro-4-hydroxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00185
Nonexistence 3-chloro-4-hydroxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00186
Nonexistence 3-bromo-4-hydroxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00187
Nonexistence 2-methyl-4-bromophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00188
Nonexistence 3-methyl-4-bromophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00189
Nonexistence n-propyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00190
Nonexistence n-butyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00191
Nonexistence 4-ethoxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00192
Nonexistence 4-propoxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00193
Nonexistence 4-butoxyphenyl 3 R 3 = R 4 = H;

Table 1 A G L W Q Y J R 3 , R 4 tBOC OH Nonexistence

Figure 112005043726247-pct00194
Nonexistence 3-methoxyphenyl 3 R 3 = R 4 = H; tBOC OH Nonexistence
Figure 112005043726247-pct00195
Nonexistence 3,4-dimethoxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00196
Nonexistence 4-methoxy-1-naphthyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00197
Nonexistence 4-phenoxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00198
Nonexistence benzyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00199
Nonexistence p-phenylbenzyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00200
Nonexistence 3-chlorophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00201
Nonexistence 3-fluorophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00202
Nonexistence 3-methoxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00203
Nonexistence 3-phenoxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00204
Nonexistence 3-benzyloxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00205
Nonexistence 3-trifluoromethylphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00206
Nonexistence 4-bromophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00207
Nonexistence 4-fluorophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00208
Nonexistence 4-methoxyphenyl 3 R 3 = R 4 = H;

Table 1 A G L W Q Y J R 3 , R 4 tBOC OH Nonexistence

Figure 112005043726247-pct00209
Nonexistence 4-ethoxyphenyl 3 R 3 = R 4 = H; tBOC OH Nonexistence
Figure 112005043726247-pct00210
Nonexistence 4-trifluoromethylphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00211
Nonexistence 5-di (trifluoromethyl) phenyl) 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00212
Nonexistence 4- (N, N-dimethylamino) -3,5-di (trifluoromethyl) phenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00213
Nonexistence 2,4-dichlorophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00214
Nonexistence 3,5-dichlorophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00215
Nonexistence 3,4-dichlorophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00216
Nonexistence 2-pyridyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00217
Nonexistence 2-pyridyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00218
Nonexistence 3-pyridyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00219
Nonexistence 4-pyridyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00220
Nonexistence 4-methoxy-3-bromophenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00221
Nonexistence 4- (methylcyclopropane) phenyl 3 R 3 = R 4 = H;

Table 1 A G L W Q Y J R 3 , R 4 tBOC OH Nonexistence

Figure 112005043726247-pct00222
Nonexistence 3-chloro-4- (methylcyclopropane) phenyl 3 R 3 = R 4 = H; tBOC OH Nonexistence
Figure 112005043726247-pct00223
Nonexistence 3-chloro-4-methoxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00224
Nonexistence 3-chloro-4-ethoxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00225
Nonexistence 3-bromo-4-ethoxyphenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00226
Nonexistence 3-chloro-4- (2-hydroxyethoxy) phenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00227
Nonexistence 3-bromo-4- (2-hydroxyethoxy) phenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00228
Nonexistence 3-chloro-4- (O-allyl) phenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00229
Nonexistence 3-bromo-4- (O-allyl) phenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00230
Nonexistence 3-chloro-4- (O-CH 2 SCH 3 ) phenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00231
Nonexistence 3-chloro-4- (O-CH 2 SCH 3 ) phenyl 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00232
Q '= -CH 2-
Figure 112005043726247-pct00233
3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00234
Q '= -CH 2-
Figure 112005043726247-pct00235
3 R 3 = R 4 = H;

Table 1 A G L W Q Y J R 3 , R 4 -(C = O) -OR 1 where R 1 = cyclopentyl OH Nonexistence

Figure 112007053853814-pct00236
Nonexistence Phenyl 3 R 3 = R 4 = H; -(C = O) -OR 1 where R 1 = cyclobutyl OH Nonexistence
Figure 112007053853814-pct00237
Nonexistence Phenyl 3 R 3 = R 4 = H;
-(C = O) -OR 1 where R 1 = cyclohexyl OH Nonexistence
Figure 112007053853814-pct00238
Nonexistence Phenyl 3 R 3 = R 4 = H;
-(C = O) -OR 1 where R 1 =
Figure 112007053853814-pct00239
OH Nonexistence
Figure 112007053853814-pct00240
Nonexistence Phenyl 3 R 3 = R 4 = H;
-(C = O) -OR 1 where R 1 =
Figure 112007053853814-pct00241
OH Nonexistence
Figure 112007053853814-pct00242
Nonexistence Phenyl 3 R 3 = R 4 = H; And
-(C = O) -OR 1 where R 1 =
Figure 112007053853814-pct00243
OH Nonexistence
Figure 112007053853814-pct00244
Nonexistence Phenyl 3 R 3 = R 4 = H;
-(C = O) -R 1 where R 1 = cyclopentyl OH Nonexistence
Figure 112007053853814-pct00245
Nonexistence Phenyl 3 R 3 = R 4 = H;
-(C = O) -NH-R 1 where R 1 = cyclopentyl OH Nonexistence
Figure 112007053853814-pct00246
Nonexistence Phenyl 3 R 3 = R 4 = H;

Table 1 A G L W Q Y J R 3 , R 4 -(C = S) -NH-R 1 where R 1 = cyclopentyl OH Nonexistence

Figure 112005043726247-pct00247
Nonexistence Phenyl 3 R 3 = R 4 = H; -S (O) 2 -R 1 where R 1 = cyclopentyl OH Nonexistence
Figure 112005043726247-pct00248
Nonexistence Phenyl 3 R 3 = R 4 = H;
 tBOC -O-CH 2 -cyclopentyl Nonexistence
Figure 112005043726247-pct00249
Nonexistence Phenyl 3 R 3 = R 4 = H;
 tBOC -NHS (O) z -CH 2 -cyclopentyl Nonexistence
Figure 112005043726247-pct00250
Nonexistence Phenyl 3 R 3 = R 4 = H;
 tBOC -(C = O) -CH 2 -cyclopentyl Nonexistence
Figure 112005043726247-pct00251
Nonexistence Phenyl 3 R 3 = R 4 = H;
 tBOC -(C = O) -O-CH 2 -cyclopentyl Nonexistence
Figure 112005043726247-pct00252
Nonexistence Phenyl 3 R 3 = R 4 = H;
 tBOC -(C = O) -OH Nonexistence
Figure 112005043726247-pct00253
Nonexistence Phenyl 3 R 3 = R 4 = H;
 tBOC -(C = O) -NH-CH z -cyclopentyl Nonexistence
Figure 112005043726247-pct00254
Nonexistence Phenyl 3 R 3 = R 4 = H;
 tBOC OH -(C = O) -CH 2-
Figure 112005043726247-pct00255
Nonexistence Phenyl One R 3 = R 4 = H;
 tBOC OH -CH (CH 3 ) -CH 2-
Figure 112005043726247-pct00256
Nonexistence Phenyl One R 3 = R 4 = H;
 tBOC OH -O-
Figure 112005043726247-pct00257
Nonexistence Phenyl 0 R 3 = methyl R 4 = H;
 tBOC OH -S-
Figure 112005043726247-pct00258
Nonexistence Phenyl 0 R 3 = methyl R 4 = H;
 tBOC OH -S (O)-
Figure 112005043726247-pct00259
Nonexistence Phenyl 0 R 3 = methyl R 4 = H;
 tBOC OH -S (O) 2-
Figure 112005043726247-pct00260
Nonexistence Phenyl 0 R 3 = methyl R 4 = H;
tBOC OH -SCH 2 CH 2-
Figure 112005043726247-pct00261
Nonexistence Phenyl 0 R 3 = R 4 = CH 3 ;

Table 1 A G L W Q Y J R 3 , R 4 tBOC OH -CF 2 CH 2-

Figure 112005043726247-pct00262
Nonexistence Phenyl One R 3 = R 4 = H; tBOC OH -CFHCH 2-
Figure 112005043726247-pct00263
Nonexistence Phenyl One R 3 = R 4 = H;
 Compound of Formula (III), m = s = 1  tBOC OH Nonexistence
Figure 112005043726247-pct00264
Nonexistence Phenyl 3 R 3 = R 4 = H;

The following additional tetrazolyl macrocyclic molecules of the invention are prepared by the methods and procedures described herein. While stereochemistry is shown, the present invention is not limited to that shown stereochemically. Those skilled in the art will readily recognize that other isomers of these compounds are also within the scope of the present invention.

Figure 112005043726247-pct00265
Figure 112005043726247-pct00266
Figure 112005043726247-pct00267

Figure 112005043726247-pct00268
Figure 112005043726247-pct00269
Figure 112005043726247-pct00270

Figure 112005043726247-pct00271
Figure 112005043726247-pct00272
Figure 112005043726247-pct00273

Figure 112005043726247-pct00274
Figure 112005043726247-pct00275
Figure 112005043726247-pct00276

Figure 112005043726247-pct00277
Figure 112005043726247-pct00278
Figure 112005043726247-pct00279

Figure 112005043726247-pct00280
Figure 112005043726247-pct00281
Figure 112005043726247-pct00282

Figure 112005043726247-pct00283
Figure 112005043726247-pct00284
Figure 112005043726247-pct00285

Figure 112005043726247-pct00286
Figure 112005043726247-pct00287
Figure 112005043726247-pct00288

Figure 112005043726247-pct00289
Figure 112005043726247-pct00290
Figure 112005043726247-pct00291

Figure 112005043726247-pct00292
Figure 112005043726247-pct00293
Figure 112005043726247-pct00294

Figure 112005043726247-pct00295
Figure 112005043726247-pct00296
Figure 112005043726247-pct00297

Figure 112005043726247-pct00298
Figure 112005043726247-pct00299
Figure 112005043726247-pct00300

Figure 112005043726247-pct00301
Figure 112005043726247-pct00302
Figure 112005043726247-pct00303

Figure 112005043726247-pct00304
Figure 112005043726247-pct00305
Figure 112005043726247-pct00306

Figure 112005043726247-pct00307
Figure 112005043726247-pct00308
Figure 112005043726247-pct00309

Figure 112005043726247-pct00310
Figure 112005043726247-pct00311
Figure 112005043726247-pct00312

Figure 112005043726247-pct00313
Figure 112005043726247-pct00314
Figure 112005043726247-pct00315

Figure 112005043726247-pct00316
Figure 112005043726247-pct00317
Figure 112005043726247-pct00318

Figure 112005043726247-pct00319
Figure 112005043726247-pct00320
Figure 112005043726247-pct00321

Figure 112005043726247-pct00322
Figure 112005043726247-pct00323
Figure 112005043726247-pct00324

Figure 112005043726247-pct00325
Figure 112005043726247-pct00326
Figure 112005043726247-pct00327

Another embodiment of the present invention is a compound represented by the above-described formula (II) wherein W is a triazole or derivative thereof, or a pharmaceutically acceptable salt, ester thereof, in combination with a pharmaceutically acceptable carrier or excipient. Or prodrugs.

Another embodiment of the present invention is a compound represented by the above-mentioned formula (III) wherein W is a triazole or a derivative thereof, or a pharmaceutically acceptable salt, ester thereof, in combination with a pharmaceutically acceptable carrier or excipient. Or prodrugs.

Exemplary tetrazolyl macrocyclic compounds of the present invention and related methods are described in US Provisional Application Numbers, filed Feb. 7, 2003. (Changes to US 10 / 360,947). Representative classes of the invention include, but are not limited to, the following compounds.

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent, W is

Figure 112007053853814-pct00328
or
Figure 112007053853814-pct00329
It is selected from the group consisting of; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; And R 3 and R 4 are hydrogen;
A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent, W is
Figure 112007053853814-pct01039
or
Figure 112007053853814-pct01040
It is selected from the group consisting of; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; And R 3 and R 4 are hydrogen;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent, W is

Figure 112005043726247-pct00330
Is; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; And R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent, W is

Figure 112005043726247-pct00331
Is; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; And R 3 and R 4 are hydrogen;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent, W is

Figure 112005043726247-pct00332
or
Figure 112005043726247-pct00333
It is selected from the group consisting of; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; And R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent, W is

Figure 112005043726247-pct00334
or
Figure 112005043726247-pct00335
It is selected from the group consisting of; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; And R 3 and R 4 are hydrogen;

A is-(C = O) -OR 1 , R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl , Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; G is hydroxyl; L is absent, W is

Figure 112007053853814-pct00336
Is; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; And R 3 and R 4 are hydrogen;

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent, W is

Figure 112007053853814-pct00337
Is; X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 - alkylamino, -CH 2 - dialkylamino, -CH 2 - arylamino, -CH 2 -Diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted Aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; j = 3; m = s = 1; And R 3 and R 4 are hydrogen;

Representative compounds of the invention include, but are not limited to, the following compounds.

TABLE 2 Compounds of Formula (II), m = s = 1 A G L W j R 3 , R 4 tBOC OH Nonexistence

Figure 112007053853814-pct00338
X = Y = phenyl  3 R 3 = R 4 = H; tBOC OH Nonexistence
Figure 112007053853814-pct00339
X = Y = phenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00340
X = n-propyl Y = phenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00341
X = m-methoxyphenyl Y = p-methoxyphenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00342
X = m-bromophenyl Y = p-methoxyphenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00343
X = 1-naphthyl Y = p-methoxyphenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00344
X = 2-thienyl Y = p-phenoxyphenyl
 3 R 3 = R 4 = H;

TABLE 2 Compounds of Formula (II), m = s = 1 A G L W j R 3 , R 4 tBOC OH Nonexistence

Figure 112007053853814-pct00345
X = 3-thienyl Y = p-methoxyphenyl  3 R 3 = R 4 = H; tBOC OH Nonexistence
Figure 112007053853814-pct00346
X = 4-pyrazolyl Y = p-methoxyphenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00347
X = 3-pyridyl Y = p-methoxyphenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00348
X = 2-pyridyl Y = p-methoxyphenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00349
X = 2-thiazolyl Y = p-methoxyphenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00350
X = benzyl Y = phenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112007053853814-pct00351
X = n-butyl Y = phenyl
 3 R 3 = R 4 = H;

TABLE 2 Compounds of Formula (II), m = s = 1 A G L W j R 3 , R 4 tBOC OH Nonexistence

Figure 112005043726247-pct00352
X = n-propyl Y = n-propyl  3 R 3 = R 4 = H; tBOC OH Nonexistence
Figure 112005043726247-pct00353
X = 4- (N, N-dimethylamino) phenyl Y = phenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00354
X = (N, N-diethylamino) methyl Y = phenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00355
X = N, N-diethylaminocarbonyl Y = phenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00356
X = m-chlorophenyl Y = p-ethoxyphenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00357
X = 2-phenylethenyl Y = phenyl
 3 R 3 = R 4 = H;
tBOC OH Nonexistence Benzotriazole  3 R 3 = R 4 = H; tBOC OH Nonexistence 5,6-methylbenzotriazole  3 R 3 = R 4 = H;

TABLE 2 Compounds of Formula (II), m = s = 1 A G L W j R 3 , R 4 tBOC OH Nonexistence

Figure 112005043726247-pct00358
X = N-ethylaminocarbonyl Y = phenyl  3 R 3 = R 4 = H; -(C = 0) -OR 1 ; R 1 = cyclopentyl OH Nonexistence
Figure 112005043726247-pct00359
X = phenyl Y = phenyl
 3 R 3 = R 4 = H;
-(C = 0) -OR 1 ; R 1 = cyclobutyl OH Nonexistence
Figure 112005043726247-pct00360
X = phenyl Y = phenyl
 3 R 3 = R 4 = H;
-(C = 0) -OR 1 ; R 1 = cyclohexyl OH Nonexistence
Figure 112005043726247-pct00361
X = phenyl Y = phenyl
 3 R 3 = R 4 = H;
-(C = 0) -OR 1 ; R 1 =
Figure 112005043726247-pct00362
OH Nonexistence
Figure 112005043726247-pct00363
X = phenyl Y = phenyl
 3 R 3 = R 4 = H;
-(C = 0) -OR 1 ; R 1 =
Figure 112005043726247-pct00364
OH Nonexistence
Figure 112005043726247-pct00365
X = phenyl Y = phenyl
 3 R 3 = R 4 = H;
-(C = 0) -OR 1 ; R 1 =
Figure 112005043726247-pct00366
OH Nonexistence
Figure 112005043726247-pct00367
X = phenyl Y = phenyl
 3 R 3 = R 4 = H;
-(C = 0) -R 2 ; R 2 = cyclopentyl OH Nonexistence
Figure 112005043726247-pct00368
X = phenyl Y = phenyl
 3 R 3 = R 4 = H;
-(C = O) -NH-R 2 R 2 = cyclopentyl OH Nonexistence
Figure 112005043726247-pct00369
X = phenyl Y = phenyl
3 R 3 = R 4 = H;
R 2 = cyclopentyl OH Nonexistence
Figure 112005043726247-pct00370
X = phenyl Y = phenyl
3 R 3 = R 4 = H;
-S (O) 2 -R 2 ; R 2 = cyclopentyl OH Nonexistence
Figure 112005043726247-pct00371
X = phenyl Y = phenyl
3 R 3 = R 4 = H;

TABLE 2 Compounds of Formula (II), m = s = 1 A G L W j R 3 , R 4 -(C = 0) -OR 1 ; R 1 = cyclopentyl O-phenethyl Nonexistence

Figure 112005043726247-pct00372
X = phenyl; Y = phenyl  3 R 3 = R 4 = H; -(C = 0) -OR 1 ; R 1 = cyclopentyl -NH-phenethyl Nonexistence
Figure 112005043726247-pct00373
X = phenyl; Y = phenyl
 3 R 3 = R 4 = H;
-(C = 0) -OR 1 ; R 1 = cyclopentyl -NHS (O) 2 -phenethyl Nonexistence
Figure 112005043726247-pct00374
X = phenyl; Y = phenyl
 3 R 3 = R 4 = H;
-(C = 0) -OR 1 ; R 1 = cyclopentyl -(C = O) -OH Nonexistence
Figure 112005043726247-pct00375
X = phenyl; Y = phenyl
 3 R 3 = R 4 = H;
-(C = O) -O-R'R '= cyclopentyl -(C = O) -O-phenethyl Nonexistence
Figure 112005043726247-pct00376
X = phenyl; Y = phenyl
3 R 3 = R 4 = H
-(C = 0) -OR 1 ; R 1 = cyclopentyl -(C = O) -NH-phenethyl Nonexistence
Figure 112005043726247-pct00377
X = phenyl; Y = phenyl
 3 R 3 = R 4 = H;
-(C = 0) -OR 1 ; R 1 = cyclopentyl -(C = O) -NH-S (SO) 2 -benzyl Nonexistence
Figure 112005043726247-pct00378
X = phenyl; Y = phenyl
 3 R 3 = R 4 = H;
tBOC OH -(C = O) CH 2-
Figure 112005043726247-pct00379
X = phenyl; Y = phenyl
 One R 3 = R 4 = H;

TABLE 2 Compounds of Formula (II), m = s = 1 A G L W j R 3 , R 4 tBOC OH -CH (CH 3 ) CH 2-

Figure 112005043726247-pct00380
X = phenyl; Y = phenyl One R 3 = methyl R 4 = H; tBOC OH -O-
Figure 112005043726247-pct00381
X = phenyl; Y = phenyl
 0 R 3 = methyl R 4 = H;
tBOC OH -S-
Figure 112005043726247-pct00382
X = phenyl; Y = phenyl
 0 R 3 = methyl R 4 = H;
tBOC OH -S (O)-
Figure 112005043726247-pct00383
X = phenyl; Y = phenyl
 0 R 3 = methyl R 4 = H;
tBOC OH -S (O) 2-
Figure 112005043726247-pct00384
X = phenyl; Y = phenyl
 0 R 3 = methyl R 4 = H;
tBOC OH -SCH 2 CH 2-
Figure 112005043726247-pct00385
X = phenyl; Y = phenyl
 0 R 3 = R 4 = CH 3 ;
tBOC OH -CF 2 CH 2-
Figure 112005043726247-pct00386
X = phenyl; Y = phenyl
 One R 3 = R 4 = H;
tBOC OH -CFHCH 2-
Figure 112005043726247-pct00387
X = phenyl; Y = phenyl
One R 3 = R 4 = H;

TABLE 2 Compounds of Formula (II), m = x = 1 A G L W j R 3 , R 4 tBOC OH Nonexistence

Figure 112005043726247-pct00388
X = phenyl Y = phenyl  3 R 3 = R 4 = H; tBOC OH Nonexistence
Figure 112005043726247-pct00389
 3 R 3 = R 4 = H;
tBOC OH Nonexistence
Figure 112005043726247-pct00390
 3 R 3 = R 4 = H; And
tBOC OH Nonexistence
Figure 112005043726247-pct00391
 3 R 3 = R 4 = H;

The following additional thiazole macrocyclic molecules of the invention are prepared by the methods and procedures described herein. While stereochemistry is shown, the invention is not limited to the stereochemistry shown. Those skilled in the art will readily recognize that other isomers of these compounds are included within the scope of the present invention.

Figure 112005043726247-pct00392
Figure 112005043726247-pct00393
Figure 112005043726247-pct00394

Figure 112005043726247-pct00395
Figure 112005043726247-pct00396
Figure 112005043726247-pct00397

Figure 112005043726247-pct00398
Figure 112005043726247-pct00399
Figure 112005043726247-pct00400

Figure 112005043726247-pct00401
Figure 112005043726247-pct00402
Figure 112005043726247-pct00403

Figure 112005043726247-pct00404
Figure 112005043726247-pct00405
Figure 112005043726247-pct00406

Figure 112005043726247-pct00407
Figure 112005043726247-pct00408
Figure 112005043726247-pct00409

Figure 112005043726247-pct00410
Figure 112005043726247-pct00411
Figure 112005043726247-pct00412

Figure 112005043726247-pct00413
Figure 112005043726247-pct00414
Figure 112005043726247-pct00415

Figure 112005043726247-pct00416
Figure 112005043726247-pct00417
Figure 112005043726247-pct00418

Figure 112005043726247-pct00419
Figure 112005043726247-pct00420
Figure 112005043726247-pct00421

Figure 112005043726247-pct00422
Figure 112005043726247-pct00423
Figure 112005043726247-pct00424
Figure 112005043726247-pct00425
Figure 112005043726247-pct00426
Figure 112005043726247-pct00427

Figure 112005043726247-pct00428
Figure 112005043726247-pct00429
Figure 112005043726247-pct00430

Figure 112005043726247-pct00431
Figure 112005043726247-pct00432
Figure 112005043726247-pct00433

Figure 112005043726247-pct00434
Figure 112005043726247-pct00435
Figure 112005043726247-pct00436

Figure 112005043726247-pct00437
Figure 112005043726247-pct00438
Figure 112005043726247-pct00439

Figure 112005043726247-pct00440
Figure 112005043726247-pct00441
Figure 112005043726247-pct00442

Figure 112005043726247-pct00443
Figure 112005043726247-pct00444
Figure 112005043726247-pct00445

Figure 112005043726247-pct00446

Another embodiment of the present invention is a compound represented by the above-described formula (II) wherein W is pyridazinone or a derivative thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient, Ester or prodrug.

Another embodiment of the present invention is a compound represented by the above-described formula (III) wherein W is pyridazinone or a derivative thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient, Ester or prodrug.

Exemplary pyridazinone macrocyclic compounds of the present invention and related methods are described in US Provisional Application Numbers, filed Mar. 7, 2003. (Changes of US 10 / 384,120). Representative classes of the invention include, but are not limited to, the following compounds.

A is-(C = O) -OR 1 ; G is hydroxyl; L is absent;

j is 3;

m = s = 1, also W =

Figure 112005043726247-pct00447
; A compound of formula (II) wherein R 3 and R 4 are hydrogen.

 A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent

j is 3; m = s = 1, and wherein R 3 and R 4 are hydrogen.

A is-(C = O) -OR 1 ; L is absent; j = 3; m = s = 1; W

Figure 112005043726247-pct00448
And is also a compound of formula (III) wherein R 3 and R 4 are hydrogen.

A is-(C = O) -O-tert-butyl; G is hydroxyl; L is absent; j = 3; m = s = 1; W

Figure 112005043726247-pct00449
Wherein R 3 and R 4 are hydrogen.

Representative compounds of the invention include, but are not limited to, the following compounds.

TABLE 3 Compounds of Formula (II), W =

Figure 112005043726247-pct00450
And m = s = 1 A G L X, Y Z j R 3 , R 4  tBOC OEt Nonexistence X = Y = Bromo Hydrogen  3 R 3 = R 4 = hydrogen;  tBOC OEt Nonexistence X = Y = thiophen-3-yl Hydrogen  3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = Y = thiophen-3-yl Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = Y = phenyl Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = Y = 4- (N, N-dimethylamino) phenyl Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = Y = 4- (trifluoromethoxy) phenyl Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = Y = 4- (methanesulfonyl) phenyl Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = Y = 4- (cyano) phenyl Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = Y = 3-pyridyl Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = Y = 4- (morpholin-4-yl-methanonyl) phenyl Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = Y = Bromo Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X and Y together = phenyl 4-methoxyphenyl 3 R 3 = R 4 = hydrogen;

TABLE 3 Compounds of Formula (II), W =

Figure 112005043726247-pct00451
And m = s = 1 A G L X, Y Z j R 3 , R 4  tBOC OH Nonexistence X and Y together = phenyl 4-chlorophenyl  3 R 3 = R 4 = hydrogen;  tBOC O Nonexistence X = 4-fluorophenyl Y = hydrogen Phenyl  3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence Y = 1-piperidyl, X = hydrogen Phenyl 3 R 3 = R 4 = hydrogen;  tBOC OEt Nonexistence X = Hydrogen Y = Bromo Phenyl 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = hydrogen Y = thiophen-3-yl Phenyl 3 R 3 = R 4 = hydrogen;  tBOC OEt Nonexistence X = bromo Y = pyrrolid-1-yl Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = thiophen-3-yl Y = pyrrolid-1-yl Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OEt Nonexistence X = Bromo Y = Azido Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OEt Nonexistence X = thiophen-3-yl Y = azido Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = thiophen-3-yl Y = azido Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = thiophen-3-yl Y = tetrazol-2-yl Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = Y = mercapto-2-pyrimidine Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = bromo Y = mercapto-2-pyrimidine Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = thiophen-3-yl Y = mercapto-2-pyrimidine Hydrogen 3 R 3 = R 4 = hydrogen;

TABLE 3 Compounds of Formula (II), W =

Figure 112005043726247-pct00452
And m = s = 1 A G L X, Y Z j R 3 , R 4  tBOC OH Nonexistence X = Y = thiazol-2-yl Hydrogen  3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = Y = imidazol-1-yl Hydrogen  3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X = 2- (cyclopropylamino) -thiazol-4-ylY = 4-methoxyphenyl Hydrogen 3 R 3 = R 4 = hydrogen;  tBOC OH Nonexistence X and Y together = 6-methoxyisoquinolinyl Hydrogen 3 R 3 = R 4 = hydrogen;

TABLE 3 Compounds of Formula (II), W =

Figure 112005043726247-pct00453
And m = s = 1 A G L X, Y Z j R 3 , R 4 -(C = O) -OR 1 where R 1 = cyclopentyl OH Nonexistence X = Y = thiophen-3-yl Hydrogen  3 R 3 = R 4 = hydrogen; -(C = O) -OR 1 where R 1 = cyclobutyl OH Nonexistence X = Y = thiophen-3-yl Hydrogen  3 R 3 = R 4 = hydrogen; -(C = O) -OR 1 where R 1 = cyclohexyl OH Nonexistence X = Y = thiophen-3-yl Hydrogen 3 R 3 = R 4 = hydrogen; -(C = O) -OR 1 where R 1 =
Figure 112005043726247-pct00454
OH Nonexistence X = Y = thiophen-3-yl Hydrogen 3 R 3 = R 4 = hydrogen;
-(C = O) -OR 1 where R 1 =
Figure 112005043726247-pct00455
OH Nonexistence X = Y = thiophen-3-yl Hydrogen 3 R 3 = R 4 = hydrogen;
-(C = O) -OR 1 where R 1 =
Figure 112005043726247-pct00456
OH Nonexistence X = Y = thiophen-3-yl Hydrogen 3 R 3 = R 4 = hydrogen;

TABLE 3 Compounds of Formula (II), W =

Figure 112005043726247-pct00457
And m = s = 1 A G L X, Y Z j R 3 , R 4  tBOC OH -(C = O) CH 2- X = Y = thiophen-3-yl Z = hydrogen  One R 3 = R 4 = hydrogen; tBOC OH -CH (CH 3 ) CH 2- X = Y = thiophen-3-yl Z = hydrogen One R 3 = methyl and R 4 = hydrogen;  tBOC OH -O- X = Y = thiophen-3-yl Z = hydrogen  0 R 3 = methyl and R 4 = hydrogen;  tBOC OH -S- X = Y = thiophen-3-yl Z = hydrogen  0 R 3 = methyl and R 4 = hydrogen;  tBOC OH -S (O)- X = Y = thiophen-3-yl Z = hydrogen  2 R 3 = methyl and R 4 = hydrogen;  tBOC OH -S (O) 2- X = Y = thiophen-3-yl Z = hydrogen  2 R 3 = methyl and R 4 = hydrogen;  tBOC OH -SCH 2 CH 2- X = Y = thiophen-3-yl Z = hydrogen  0 R 3 = R 4 = CH 3 ;  tBOC OH -CF 2 CF 2- X = Y = thiophen-3-yl Z = hydrogen  One R 3 = R 4 = hydrogen;  tBOC OH -CFHCH 2- X = Y = thiophen-3-yl Z = hydrogen  One R 3 = R 4 = hydrogen;

TABLE 3 Compounds of Formula (II), W =

Figure 112005043726247-pct00458
And m = s = 1 A G L X, Y Z j R 3 , R 4 -(C = O) -OR 1 R 1 = cyclopentyl -O-phenethyl Nonexistence X = Y = thiophen-3-yl Z = hydrogen 3 R 3 = R 4 = hydrogen; -(C = O) -OR 1 R 1 = cyclopentyl -NH-phenethyl Nonexistence X = Y = thiophen-3-yl Z = hydrogen 3 R 3 = R 4 = hydrogen; -(C = O) -OR 1 R 1 = cyclopentyl -NHS (O) 2 -phenethyl Nonexistence X = Y = thiophen-3-yl Z = hydrogen 3 R 3 = R 4 = hydrogen; -(C = O) -OR 1 R 1 = cyclopentyl -(C = O) -OH Nonexistence X = Y = thiophen-3-yl Z = hydrogen 3 R 3 = R 4 = hydrogen; -(C = O) -OR 1 R 1 = cyclopentyl -(C = O) -O-phenethyl Nonexistence X = Y = thiophen-3-yl Z = hydrogen 3 R 3 = R 4 = hydrogen; -(C = O) -OR 1 R 1 = cyclopentyl -(C = O) -NH-phenethyl Nonexistence X = Y = thiophen-3-yl Z = hydrogen 3 R 3 = R 4 = hydrogen; -(C = O) -OR 1 R 1 = cyclopentyl -(C = O) -NH-S (O) 2 -benzyl Nonexistence X = Y = thiophen-3-yl Z = hydrogen 3 R 3 = R 4 = hydrogen;

The following additional thiazole macrocyclic molecules of the invention are prepared by the methods and procedures described herein. While stereochemistry is shown, the invention is not limited to the stereochemistry shown. Those skilled in the art will readily recognize that other isomers of these compounds are also within the scope of the present invention.

Figure 112005043726247-pct00459
Figure 112005043726247-pct00460
Figure 112005043726247-pct00461

Figure 112005043726247-pct00462
Figure 112005043726247-pct00463
Figure 112005043726247-pct00464

Figure 112005043726247-pct00465

Figure 112005043726247-pct00466

Figure 112005043726247-pct00467

Additional compounds of the invention are those of formula (I), wherein W is benzimidazolyl, wherein benzimidazolyl is substituted with one or two heteroaryl groups, each of which may be independently substituted, II) or (III).

Figure 112005043726247-pct00468

Figure 112005043726247-pct00469

According to another embodiment, the pharmaceutical compositions of the present invention may further contain other anti-HCV agents. Examples of anti-HCV agents include, but are not limited to, α-interferon, β-interferon, ribavirin, and amantadine.

According to yet another embodiment, the pharmaceutical compositions of the present invention may further comprise other HCV proteinase inhibitors.

According to another embodiment, the pharmaceutical composition of the present invention includes, but is not limited to, inhibitor (s) of other targets in the HCV life cycle, including but not limited to helicase, polymerase, metalloprotease, and internal ribosomal entry site (IRES). It may further include.

According to a further embodiment, the present invention includes a method of treating an infection of hepatitis C in a subject in need thereof by administering to the subject an anti-HCV viral effective amount of a pharmaceutical compound or composition of the invention. The method further comprises administration of additional therapeutic agent, including another antiviral agent or anti-HCV agent. Additional agents may be co-administered, simultaneously administered or staged with the compounds or compositions described herein. The method may further comprise identifying a subject in need of treatment for a hepatitis C infection. The confirmation can be an objective (eg, health care provider administration) or a subjective (eg diagnostic test) means.

All documents, including patents, patent publications, articles, books, and the like, described throughout the specification are hereby incorporated by reference in their entirety.

Justice

The following definitions of various terms and phrases used to describe the invention are used throughout the specification and claims unless otherwise limited to specific examples, either individually or as part of a larger group, and are consistent with conventional use in the art and Applies to terms.

The term "C x -C y " as used herein is used together with the name of a carbon-containing group, indicating that the group contains x to y carbon atoms, where x and y are integers.

As used herein, the terms "halo" and "halogen" refer to atoms selected from fluorine, chlorine, bromine and iodine.

The term "alkyl" as used herein refers to a saturated, straight-chain or branched hydrocarbon radical. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, octyl, decyl, dodecyl radicals.

The term "substituted alkyl" as used herein refers to F, Cl, Br, I, OH, NO 2 , CN, C 1 -C 6 -alkyl-OH, C (O) C 1 -C 6 -alkyl, OCH 2- (C 3 -C 12 -cycloalkyl), C (O) -aryl, C (O) -heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2 -heteroaryl, CONH 2 , CONH- (C 1 -C 6 -alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C 1 -C 6 -alkyl), OC (O) -aryl, OC (O) -heteroaryl, OCO 2 -alkyl , OCO 2 -aryl, OCO 2 -heteroaryl, CONH 2 , OCONH- (C 1 -C 6 -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C 1 -C 6 -alkyl) , NHC (O) -aryl, NHC (O) -heteroaryl, NHCONH-aryl, NHCONH-heteroaryl, SO 2 -C 1 -C 6 -alkyl, SO 2 -alkyl, C 3 -C 6 -cycloalkyl, CF 3 , CH 2 CF 3 , CHCl 2 , CH 2 NH 2 , CH 2 SO 2 CH 3 H, haloalkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl , Arylalkyl, heteroalkyl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C 1 -C 6 -Alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C 1 -C 3 -alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C 1 -C 6 -alkylthio, or methylalkyl, refers to an "alkyl" group substituted by independent substitution of one or more (eg 1, 2, or 3) hydrogen atoms.

As used herein, "haloalkyl" refers to acyclic, straight or branched chain alkyl with one or more hydrogens substituted with halogen selected from bromo, chloro, fluoro or iodine.

As used herein, "thioalkyl" refers to acyclic, straight or branched chain alkyl substituents containing, for example, thiol groups and non-limiting thiopropyl.

As used herein, "alkoxy" refers to the aforementioned alkyl group attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.

The term "alkenyl" as used herein denotes a monovalent group derived by the removal of a single hydrogen atom from a hydrocarbon moiety having at least one carbon-carbon double atom. Alkenyl includes, but is not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl and the like.

The term "substituted alkenyl" as used herein refers to F, Cl, Br, I, OH, NO 2 , CN, C 1 -C 6 -alkyl-OH, C (O)-(C 1 -C 6 -alkyl) , OCH 2- (C 3 -C 12 -cycloalkyl), C (O) -aryl, C (O) -heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2 -heteroaryl, CONH 2 , CONH -C 1 -C 6 -alkyl, CONH-aryl, CONH-heteroaryl, OC (O)-(C 1 -C 6 -alkyl), OC (O) -aryl, OC (O) -heteroaryl, OCO 2 -alkyl, 2 OCO-aryl, OCO 2 - heteroaryl, OCONH 2, OCONH-C 1 -C 6 - alkyl, OCONH- aryl, OCONH- heteroaryl, NHC (O) -C 1 -C 6 -alkyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHCO 2 -alkyl, NHCO 2 -aryl, NHCO 2 -heteroaryl, NHCONH 2 , NHCONH- (C 1 -C 6 -alkyl), NHCONH-aryl, NHCONH -Heteroaryl, SO 2- (C 1 -C 6 alkyl), SO 2 aryl, SO 2 -heteroaryl, SO 2 NH 2 , SO 2 -NH- (C 1 -C 6 alkyl), SO 2 NH-aryl , SO 2 NH-heteroaryl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, CF 3 , CH 2 CF 3 , CHCl 2 , CH 2 NH 2 , CH 2 SO 2 CH 3 H, haloalkyl, C 3 -C 12 cycloalkyl, Hwandoen C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C 1 -C 6 - alkoxy, methoxy Methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C 1 -C 3 -alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C 1 -C 6- Reference is made to an "alkenyl" group substituted by alkylthio, or methylthiomethyl, by one or more independent substitutions of one or more hydrogen atoms.

The term "alkynyl" as used herein denotes a monovalent group derived by the removal of a single hydrogen atom from a hydrocarbon moiety having at least one carbon-carbon triple bond. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl and the like.

The term "substituted alkynyl" as used herein refers to F, Cl, Br, I, OH, NO 2 , CN, C 1 -C 6 -alkyl-OH, C (O)-(C 1 -C 6 -alkyl) , OCH 2- (C 3 -C 12 -cycloalkyl), C (O) -aryl, C (O) -heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2 -heteroaryl, CONH 2 , CONH -(C 1 -C 6 -alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C 1 -C 6 -alkyl), OC (O) -aryl, OC (O) -heteroaryl, OCO 2 -alkyl, OCO 2 -aryl, OCO 2 -heteroaryl, OCONH 2 , OCONH- (C 1 -C 6 -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C 1 -C 6 -alkyl), NHC (O) -aryl, NHC (O) -heteroaryl, NHCO 2 -alkyl, NHCO 2 -aryl, NHCO 2 -heteroaryl, NHCONH 2 , NHCONH- (C 1 -C 6 -alkyl) , NHCONH-aryl, NHCONH-heteroaryl, SO 2- (C 1 -C 6 alkyl), SO 2 aryl, SO 2 -heteroaryl, SO 2 NH 2 , SO 2 -NH- (C 1 -C 6 alkyl) , SO 2 NH-aryl, SO 2 NH-heteroaryl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, CF 3 , CH 2 CF 3 , CHCl 2 , CH 2 NH 2 , CH 2 SO 2 CH 3 H, haloalkyl, C 3 -C 12 cycloal Ke, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C 1 -C 6- Alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C 1 -C 3 -alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C 1- Reference is made to C 6 -alkylthio, or “alkynyl” groups substituted by one or more independent substitutions of hydrogen atoms with methylthiomethyl.

As used herein, the term “aryl” refers to a mono or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl, and the like. To mention.

The term "substituted aryl" as used herein refers to F, Cl, Br, I, OH, NO 2 , CN, C 1 -C 6 -alkyl-OH, C (O)-(C 1 -C 6 -alkyl), OCH 2- (C 3 -C 12 -cycloalkyl), C (O) -aryl, C (O) -heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2 -heteroaryl, CONH 2 , CONH- (C 1 -C 6 -alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C 1 -C 6 -alkyl), OC (O) -aryl, OC (O) -heteroaryl, OCO 2 -alkyl, OCO 2 -aryl, OCO 2 -heteroaryl, OCONH 2 , OCONH- (C 1 -C 6 -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C 1 -C 6 -Alkyl), NHC (O) -aryl, NHC (O) -heteroaryl, NHCO 2 -alkyl, NHCO 2 -aryl, NHCO 2 -heteroaryl, NHCONH 2 , NHCONH- (C 1 -C 6 -alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO 2- (C 1 -C 6 alkyl), SO 2 aryl, SO 2 -heteroaryl, SO 2 NH 2 , SO 2 -NH- (C 1 -C 6 alkyl), SO 2 NH-aryl, SO 2 NH-heteroaryl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, CF 3 , CH 2 CF 3 , CHCl 2 , CH 2 NH 2 , CH 2 SO 2 CH 3 H, C 1 -C 6 alkyl, halo alkyl, C 3 -C 12 Cycle as alkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C 1 -C 6 -alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C 1 -C 3 -alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C It refers to an "aryl" group substituted by 1 -C 6 -alkylthio, or methylthiomethyl, by one or more independent substitutions of a hydrogen atom.

As used herein, the term “arylalkyl” refers to a C 1 -C 3 alkyl or C 1 -C 6 alkyl moiety attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl, and the like.

The term "substituted arylalkyl" as used herein refers to F, Cl, Br, I, OH, NO 2 , CN, C 1 -C 6 -alkyl-OH, C (O)-(C 1 -C 6 -alkyl) , OCH 2- (C 3 -C 12 -cycloalkyl), C (O) -aryl, C (O) -heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2 -heteroaryl, CONH 2 , CONH -(C 1 -C 6 -alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C 1 -C 6 -alkyl), OC (O) -aryl, OC (O) -heteroaryl, OCO 2 -alkyl, OCO 2 -aryl, OCO 2 -heteroaryl, OCONH 2 , OCONH- (C 1 -C 6 -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C 1 -C 6 -alkyl), NHC (O) -aryl, NHC (O) -heteroaryl, NHCO 2 -alkyl, NHCO 2 -aryl, NHCO 2 -heteroaryl, NHCONH 2 , NHCONH- (C 1 -C 6 -alkyl) , NHCONH-aryl, NHCONH-heteroaryl, SO 2- (C 1 -C 6 alkyl), SO 2 aryl, SO 2 -heteroaryl, SO 2 NH 2 , SO 2 -NH- (C 1 -C 6 alkyl) , SO 2 NH-aryl, SO 2 NH-heteroaryl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, CF 3 , CH 2 CF 3 , CHCl 2 , CH 2 NH 2 , CH 2 SO 2 CH 3 H, haloalkyl, C 3 -C 12 cyclo Alkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C 1 -C 6- Alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C 1 -C 3 -alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C 1- Reference is made to the aforementioned arylalkyl groups substituted by one or more independent substitutions of a hydrogen atom with C 6 -alkylthio, or methylthiomethyl.

The term "cycloalkyl" as used herein denotes a monovalent group derived by the removal of a single hydrogen atom from a mono-cyclic or bicyclic saturated carbocyclic ring. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.

The term "substituted cycloalkyl" as used herein refers to F, Cl, Br, I, OH, NO 2 , CN, C 1 -C 6 -alkyl-OH, C (O)-(C 1 -C 6 -alkyl) , OCH 2- (C 3 -C 12 -cycloalkyl), C (O) -aryl, C (O) -heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2 -heteroaryl, CONH 2 , CONH -(C 1 -C 6 -alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C 1 -C 6 -alkyl), OC (O) -aryl, OC (O) -heteroaryl, OCO 2 -alkyl, OCO 2 -aryl, OCO 2 -heteroaryl, OCONH 2 , OCONH- (C 1 -C 6 -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C 1 -C 6 -alkyl), NHC (O) -aryl, NHC (O) -heteroaryl, NHCO 2 -alkyl, NHCO 2 -aryl, NHCO 2 -heteroaryl, NHCONH 2 , NHCONH- (C 1 -C 6 -alkyl) , NHCONH-aryl, NHCONH-heteroaryl, SO 2- (C 1 -C 6 alkyl), SO 2 aryl, SO 2 -heteroaryl, SO 2 NH 2 , SO 2 -NH- (C 1 -C 6 alkyl) , SO 2 NH-aryl, SO 2 NH-heteroaryl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, CF 3 , CH 2 CF 3 , CHCl 2 , CH 2 NH 2 , CH 2 SO 2 CH 3 H, C 1 -C 6 alkyl, haloalkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C 1 -C 6 -alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C 1 -C 3 -alkylamino, thio, aryl-thio, heteroarylthio, benzyl Reference is made to the aforementioned "cycloalkyl" groups substituted by one, two or three independent substitutions of hydrogen atoms with -thio, C 1 -C 6 -alkylthio, or methylthiomethyl.

As used herein, the terms "heterocyclo" and "heterocyclic" refer to a 3-7 membered saturated or unsaturated (including aromatic) cycle having 1-4 non-carbon ring atoms selected from heteroatoms consisting of N, O, and S. Mention is made of monovalent substituents derived by the removal of hydrogen from hydrogen. Examples of suitable heterocycles include, but are not limited to, tetrahydrofuran, thiophene, diazepine, isoxazole, piperidine, dioxane, morpholine, and pyrimidine. The term also refers to heterocycles fused to one or more other cycles, whether hetero or carbocyclic. One example is thiazolo [4.5-b] -pyridine. The terms "heterocycloalkyl", "aliphatic heteromonocyclic ring system", "aliphatic heterobicyclic ring system", "aliphatic heterocyclic ring system", "heteroaryl", "aromatic heteromonocyclic ring system" , "Aromatic heterobicyclic ring system", "aromatic heterocyclic ring system", "heteroarylalkyl" are generally included in the term "heterocycle", but the specific meaning thereof is described in more detail.

The term "heterocycloalkyl" as used herein refers to a bi- or tri-cyclic group or non-aromatic 5-, including a fused six-membered ring having 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen. , 6- or 7-membered ring, wherein (i) each 5-membered ring has 0 to 1 double bond and each 6-membered ring has 0 to 2 double bonds, (ii) Nitrogen and sulfur heteroatoms may be optionally oxidized; (iii) nitrogen heteroatoms may optionally be quaternized; And (iv) any one of the heterocyclic rings may be fused to the benzene ring. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imizazolinyl, amizazolidinyl, piperidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, Thiazolidinyl, isothiazolidinyl and hydrofuryl.

The term "substituted heterocycloalkyl" as used herein refers to F, Cl, Br, I, OH, NO 2 , CN, C 1 -C 6 -alkyl-OH, C (O)-(C 1 -C 6 -alkyl ), OCH 2- (C 3 -C 12 -cycloalkyl), C (O) -aryl, C (O) -heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2 -heteroaryl, CONH 2 , CONH- (C 1 -C 6 -alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C 1 -C 6 -alkyl), OC (O) -aryl, OC (O) -heteroaryl , OCO 2 -alkyl, OCO 2 -aryl, OCO 2 -heteroaryl, OCONH 2 , OCONH- (C 1 -C 6 -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C 1- C 6 -alkyl), NHC (O) -aryl, NHC (O) -heteroaryl, NHCO 2 -alkyl, NHCO 2 -aryl, NHCO 2 -heteroaryl, NHCONH 2 , NHCONH- (C 1 -C 6 -alkyl ), NHCONH-aryl, NHCONH-heteroaryl, SO 2- (C 1 -C 6 alkyl), SO 2 aryl, SO 2 -heteroaryl, SO 2 NH 2 , SO 2 -NH- (C 1 -C 6 alkyl ), SO 2 NH-aryl, SO 2 NH-heteroaryl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, CF 3 , CH 2 CF 3 , CHCl 2 , CH 2 NH 2 , CH 2 SO 2 CH 3 H, C 1 -C 6 alkyl, Alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryl, Oxy, C 1 -C 6 -alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C 1 -C 3 -alkylamino, thio, aryl-thio, heteroarylthio Reference is made to the aforementioned heterocycloalkyl groups substituted by one or more independent substitutions of a hydrogen atom with benzyl-thio, C 1 -C 6 -alkylthio, or methylthiomethyl.

As used herein, the term “aliphatic heteromonocyclic ring system” means a ring system containing a non-aromatic ring comprising at least one ring hetero (ie, not carbon) atom selected from oxygen, nitrogen and sulfur. do. The term “aliphatic heterobicyclic ring system” means a ring system having two fused rings, wherein at least one ring is at least one ring hetero (ie, not carbon) selected from oxygen, nitrogen, and sulfur ) Non-aromatic ring containing atoms. The term “aliphatic heterotricyclic ring system” means a ring system having three fused rings, wherein at least one ring is at least one ring hetero (ie, not carbon) selected from oxygen, nitrogen, and sulfur ) Non-aromatic ring containing atoms. As will be appreciated, aliphatic heterocyclic ring systems can have any degree of saturation (ie, double or triple bond), wherein any heteroatom-containing constituent ring is not aromatic. Thus, structures such as indolin (having a non-aromatic heterocyclic ring (ie, pyrroline ring) fused to an aromatic carbocyclic ring (specifically a phenyl ring)) and phthalimide are "aliphatic heterobicyclic Ring system ".

As used herein, the term “aromatic heteromonocyclic ring system” means an aromatic ring comprising at least one ring hetero (ie, not carbon) atom selected from oxygen, nitrogen and sulfur. The term "aromatic heterobicyclic ring system" means an aromatic ring system having two fused rings and includes at least one ring hetero (ie, not carbon) atom selected from oxygen, nitrogen and sulfur. The term "aromatic heterotricyclic ring system" means a ring system having three fused rings and includes at least one ring hetero (ie, not carbon) atom selected from oxygen, nitrogen and sulfur. Substituent atoms of an aromatic heterocyclic ring system, together with additional atoms, may form a further fused ring structure that is not aromatic. Thus, 5,6,7,8 tetrahydroisoquinoline is an example of an aromatic heterobicyclic ring system, while 1,2,3,4 tetrahydroisoquinoline is an example of an aliphatic heterobicyclic ring system.

As used herein, the term “heteroaryl” means a cyclic aromatic radical having 5 to 10 ring atoms, at least one ring atom being selected from sulfur, oxygen and nitrogen, the remaining ring atoms being carbon, and radicals For example, pyridinyl, pyrazinyl, pyrimidyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazoyl, isooxazoyl, thiadiazoyl, oxadiazoyl, thiophenyl, furan Bond through ring atoms such as one, quinolinyl, and the like.

As used herein, the term “substituted heteroaryl” means a heteroaryl group as defined herein, wherein one, two or three hydrogen atoms are selected from F, Cl, Br, I, OH, NO 2 , CN, C 1 -C 6 -Alkyl-OH, C (O) -C 1 -C 6 -alkyl, OCH 2- (C 3 -C 12 -cycloalkyl), C (O) -aryl, C (O) -heteroaryl, CO 2- Alkyl, CO 2 -aryl, CO 2 -heteroaryl, CONH 2 , CONH- (C 1 -C 6 -alkyl), CONH-aryl, CONH-heteroaryl, OC (O) -C 1 -C 6 -alkyl, OC (O) -aryl, OC (O) -heteroaryl, OCO 2 -alkyl, OCO 2 -aryl, OCO 2 -heteroaryl, OCONH 2 , OCONH- (C 1 -C 6 -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C 1 -C 6 -alkyl), NHC (O) -aryl, NHC (O) -heteroaryl, NHCO 2 -alkyl, NHCO 2 -aryl, NHCO 2 -heteroaryl , NHCONH 2 , NHCONH- (C 1 -C 6 -alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO 2- (C 1 -C 6 -alkyl), SO 2 -aryl, SO 2 -heteroaryl, SO 2 NH 2 , SO 2 NH- (C 1 -C 6 -alkyl), SO 2 NH-aryl, SO 2 NH-heteroaryl, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, CF 3 , CH 2 CF 3 , CHCl 2 , CH 2 NH 2 , CH 2 SO 2 CH 3 H, C 1 -C 6 -alkyl, haloalkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C 1 -C 6 -alkoxy, methoxymethoxy, methoxyethoxy, amino, benzyl Independently substituted with amino, arylamino, heteroarylamino, C 1 -C 3 -alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C 1 -C 6 -alkyl-thio, or methylthiomethyl It is.

As used herein, the term “heteroarylalkyl” refers to a C 1 -C 3 alkyl or C 1 -C 6 alkyl moiety attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like.

As used herein, the term "substituted heteroarylalkyl", as described above, includes one or more hydrogen atoms of F, Cl, Br, I, OH, NO 2 , CN, C 1 -C 6 -alkyl-OH, C (O ) -C 1 -C 6 -alkyl, OCH 2- (C 3 -C 12 -cycloalkyl), C (O) -aryl, C (O) -heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2- heteroaryl, CONH 2 , CONH- (C 1 -C 6 -alkyl), CONH-aryl, CONH-heteroaryl, OC (O) -C 1 -C 6 -alkyl, OC (O) -aryl, OC (O) -heteroaryl, OCO 2 -alkyl, OCO 2 -aryl, OCO 2 -heteroaryl, OCONH 2 , OCONH- (C 1 -C 6 -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O )-(C 1 -C 6 -alkyl), NHC (O) -aryl, NHC (O) -heteroaryl, NHCO 2 -alkyl, NHCO 2 -aryl, NHCO 2 -heteroaryl, NHCONH 2 , NHCONH- (C 1 -C 6 -alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO 2- (C 1 -C 6 -alkyl), SO 2 -aryl, SO 2 -heteroaryl, SO 2 NH 2 , SO 2 NH- (C 1 -C 6 -alkyl), SO 2 NH-aryl, SO 2 NH-heteroaryl, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, CF 3 , CH 2 CF 3 , CHCl 2 , CH 2 NH 2 , CH 2 SO 2 CH 3 H, C 1 -C 6 -alkyl, haloalkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C 1 -C 6 -alkoxy, methoxymethoxy, methoxyethoxy, amino, benzyl Independently substituted with amino, arylamino, heteroarylamino, C 1 -C 3 -alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C 1 -C 6 -alkyl-thio, or methylthiomethyl Heteroarylalkyl group.

Substituents substituted on any of the groups described herein (eg, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocyclic) are also -F, -Cl, -Br , -I, -OH, protected hydroxy, aliphatic ethers, aromatic ethers, oxo, -NO 2 , -CN, -C 1 -C 12 -alkyl optionally substituted with halogen (such as perhaloalkyls) , optionally substituted by halogen, C 2 -C 12 -alkenyl, optionally substituted by halogen, C 2 -C 12 - alkynyl, -NH 2, protected amino, NH-C 1 -C 12 - alkyl, NH-C 2 -C 12 -alkenyl, NH-C 2 -C 12 -alkynyl, NH-C 3 -C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -di Alkylamino, -diarylamino, -diheteroarylamino, OC 1 -C 12 -alkyl, OC 2 -C 12 -alkenyl, OC 2 -C 12 -alkynyl, OC 3 -C 12 -cycloalkyl, O -Aryl, O-heteroaryl, O-heterocycloalkyl, C (O) -C 1 -C 12 -alkyl, C (O) -C 2 -C 12 -alkenyl, C (O) -C 2 -C 12 -alkynyl, C (O) -C 3 -C 12 -cycloalkyl, C (O) -aryl, C (O) -heteroaryl, C ( O) -heterocycloalkyl, -CONH 2 , -CONH-C 1 -C 12 -alkyl, -CONH-C 2 -C 12 -alkenyl, -CONH-C 2 -C 12 -alkynyl, -CONH-C 3 -C 12 -cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -CO 2 -C 1 -C 12 -alkyl, -CO 2 -C 2 -C 12 -alkenyl , -CO 2 -C 2 -C 12 -alkynyl, -CO 2 -C 3 -C 12 -cycloalkyl, -CO 2 -aryl, -CO 2 -heteroaryl, -CO 2 -heterocycloalkyl, -OCO 2 -C 1 -C 12 -alkyl, -OCO 2 -C 2 -C 12 -alkenyl, -OCO 2 -C 2 -C 12 -alkynyl, -OCO 2 -C 3 -C 12 -cycloalkyl,- OCO 2 -aryl, -OCO 2 -heteroaryl, -OCO 2 -heterocycloalkyl, -OCONH 2 , -OCONH-C 1 -C 12 -alkyl, -OCONH-C 2 -C 12 -alkenyl, -OCONH- C 2 -C 12 -alkynyl, -OCONH-C 3 -C 12 -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC (O) -C 1 -C 12 -Alkyl, -NHC (O) -C 2 -C 1 2 -alkenyl, -NHC (O) -C 2 -C 12 -alkynyl, -NHC (O) -C 3 -C 12 -cycloalkyl, -NHC (O) -aryl, -NHC (O) -hetero Aryl, -NHC (O) -heterocycloalkyl, -NHCO 2 -C 1 -C 12 -alkyl, -NHCO 2 -C 2 -C 12 -alkenyl, -NHCO 2 -C 2 -C 12 -alkynyl, -NHCO 2 -C 3 -C 12 -cycloalkyl, -NHCO 2 -aryl, -NHCO 2 -heteroaryl, -NHCO 2 -heterocycloalkyl, -NHC (O) NH 2, -NHC (O) NH-C 1- C 12 -alkyl, -NHC (O) NH-C 2 -C 12 -alkenyl, -NHC (O) NH-C 2 -C 12 -alkynyl, -NHC (O) NH-C 3 -C 12 -cycloalkyl, -NHC (O) NH-aryl, -NHC (O) NH-heteroaryl, -NHC (O) NH-heterocycloalkyl, -NHC (S) NH 2, -NHC (S) NH- C 1 -C 12 -alkyl, -NHC (S) NH-C 2 -C 12 -alkenyl, -NHC (S) NH-C 2 -C 12 -alkynyl, -NHC (S) NH-C 3- C 12 -cycloalkyl, -NHC (S) NH-aryl, -NHC (S) NH-heteroaryl, -NHC (S) NH-heterocycloalkyl, -NHC (NH) NH 2, -NHC (NH) NH -C 1 -C 12 - alkyl, -NHC (NH) NH-C 2 -C 12 - alkenyl, -NHC (NH) NH-C 2 -C 12 - alkynyl, -NHC (NH) NH-C 3 -C 12 - cycloalkyl, -NHC (NH) NH- O , -NHC (NH) NH- heteroaryl, -NHC (NH) NH- heterocycloalkyl, -NHC (NH) -C 1 -C 12 - alkyl, -NHC (NH) -C 2 -C 12 - alkenyl, , -NHC (NH) -C 2 -C 12 -alkynyl, -NHC (NH) -C 3 -C 12 -cycloalkyl, -NHC (NH) -aryl, -NHC (NH) -heteroaryl, -NHC (NH) -heterocycloalkyl, -C (NH) NH-C 1 -C 12 -alkyl, -C (NH) NH-C 2 -C 12 -alkenyl, -C (NH) NH-C 2 -C 12 -alkynyl, -C (NH) NH-C 3 -C 12 -cycloalkyl, -C (NH) NH-aryl, -C (NH) NH-heteroaryl, -C (NH) NH-heterocycloalkyl , -S (O) -C 1 -C 12 -alkyl, -S (O) -C 2 -C 12 -alkenyl, -S (O) -C 2 -C 12 -alkynyl, -S (O) -C 3 -C 12 -cycloalkyl, -S (O) -aryl, -S (O) -heteroaryl, -S (O) -heterocycloalkyl, -SO 2 NH 2 , -SO 2 NH-C 1 -C 12 -alkyl, -SO 2 NH-C 2 -C 12 -alkenyl, -SO 2 NH-C 2 -C 12 -alkynyl, -SO 2 NH-C 3 -C 12 -cycloalkyl, -SO 2 NH-aryl, -SO 2 NH-heteroaryl, -SO 2 NH-heterocycloalkyl, -NHSO 2 -C 1 -C 12 -alkyl, -NHSO 2 -C 2 -C 12 -alkenyl, -NHSO 2 -C 2 -C 12 -alkynyl, -N HSO 2 -C 3 -C 12 -cycloalkyl, -NHSO 2 -aryl, -NHSO 2 -heteroaryl, -NHSO 2 -heterocycloalkyl, -CH 2 NH 2 , -CH 2 SO 2 CH 3 , -aryl, -Arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C 3 -C 12 -cycloalkyl, -polyalkoxyalkyl, -polyalkoxy, -methoxymethoxy, -methoxyethoxy,- SH, -SC 1 -C 12 -alkyl, -SC 2 -C 12 -alkenyl, -SC 2 -C 12 -alkynyl, -SC 3 -C 12 -cycloalkyl, -S-aryl, -S-hetero Aryl, -S-heterocycloalkyl, or methylthiomethyl. Aryls, heteroaryls, alkyls and the like can also be further substituted.

The term "alkylamino" as used herein refers to a group having the structure -NH (C 1 -C 12 -alkyl), wherein C 1 -C 12 -alkyl is as described above. The term "dialkylamino" means a group having the structure -N (C 1 -C 12 -alkyl) 2 , wherein C 1 -C 12 -alkyl is as described above. Examples of dialkylamino include, but are not limited to, N, N-dimethylamino, N, N-diethylamino, N, N-methylethylamino, piperidino, and the like.

The term "diarylamino" refers to a group having a structure of N (aryl) 2 or -N (substituted aryl) 2 , wherein substituted aryl is as described above. Examples of diarylamino include, but are not limited to, N, N-diphenylamino, N, N-dinaphthylamino, N, N-di (toluenyl) amino and the like.

The term "diheteroarylamino" refers to a group having a structure of N (heteroaryl) 2 or -N (substituted heteroaryl) 2 , wherein heteroaryl and substituted heteroaryl are as described above. Examples of diheteroarylamino include, but are not limited to, N, N-difuranylamino, N, N-dithiazolidinylamino, N, N-di (imidazole) amino and the like.

The term "hydroxy protecting group" as used herein refers to labile chemicals known in the art for the purpose of protecting hydroxy groups against unwanted reactions during the synthesis process. After the above-described synthetic procedure, the hydroxy protecting group described herein is optionally removed. Hydroxy protecting groups known in the art are generally described in THGreene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). have. Examples of hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, Isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2-perfuryloxycarbonyl, alkyloxycarbonyl, Acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl 2-propenyl, 3-methyl-3-butenyl, aryl, benzyl, paramethoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl , 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsi Reel, triethylsilyl, triisopropylsilyl and the like. Preferred hydroxy protecting groups in the present invention are acetyl (Ac or -C (O) CH 3 ), benzoyl (Bn or -C (O) C 6 H 5 ) and trimethylsilyl (TMS or -Si (CH 3 ) 3 a).

The term "protected hydroxy" as used herein refers to a hydroxy group protected with the aforementioned hydroxy protecting group, including, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups.

As used herein, the term "nitrogen (or amino) protecting group" refers to labile chemicals known in the art for the purpose of protecting nitrogen groups against unwanted reactions during the synthesis process. After the above synthetic procedure, the nitrogen protecting groups described herein are optionally removed. Hydroxy protecting groups known in the art are generally T.H.Greene and P.G.M. Wuts, et al., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of nitrogen protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl and the like.

The term "protected amino" as used herein refers to an amino group protected with an amino protecting group as mentioned above.

The term “nucleophilic heterocyclic compound” means a heterocyclic group in nucleophilic form (eg, metal salt form, quantized form), and reacts with another molecule to produce two molecules (eg, nucleophilic substitution). Nucleophilic molecules in the reaction). Examples of such nucleophilic heterocyclic compounds are known in the art and are described herein.

The term "leaving group" means a chemical that can be released from a molecule during a reaction, especially a nucleophilic substitution reaction. Examples of leaving groups are halides, mesyl groups, tosyl groups, alkoxides, hydroxides and their quantized forms. Examples of such leaving groups are known in the art and are described herein.

The term "acyl" refers to, but is not limited to, moieties derived from acids such as, for example, carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and acetic acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonics, aromatic sulfonyls, aliphatic sulfinyls, aromatic phosphates and aliphatic phosphates.

As used herein, the term "aprotic solvent" refers to a solvent that is relatively inert to proton activity, i.e., does not act as a proton-donor. Examples include hydrocarbons such as hexane, toluene, halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform and the like, heterocyclic compounds such as tetra hydrofuran and N-methylferolidinone, diethyl Ethers such as ether, bis-methoxymethyl ether, and the like, but are not limited thereto. Such compounds are known to those skilled in the art, and it will be apparent to those skilled in the art that each solvent or mixture thereof is preferred for a particular compound and reaction conditions depending on requirements such as, for example, the solubility of the reagent, the activity of the reagent, and the desired temperature range. . A more detailed description of aprotic solvents can be found in organic chemistry textbooks or in special papers, such as, for example, Organic Solvents Physical Properties and Methods of Purification, 4th edition, co-authored by John A. Riddick, Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

As used herein, the term "protogenic organic solvent" means a solvent that tends to supply protons, such as, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol and the like. do. Such solvents are known to those skilled in the art, and it will be apparent to those skilled in the art that each solvent or mixture thereof is preferred for a particular compound and reaction conditions depending on requirements such as, for example, the solubility of the reagent, the activity of the reagent, and the desired temperature range. . A more detailed description of protic solvents can be found in organic chemistry textbooks or in special papers, such as, for example, Organic Solvents Physical Properties and Methods of Purification, 4th edition, co-authored by John A. Riddick, Vol. .II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The combination of substituents with the compounds envisioned by the present invention takes the form of a stable compound. As used herein, the term “stable” is sufficient to allow the compounds to be prepared and to maintain the original appearance of the compound for a sufficient time effective for the purposes described herein (ie, for therapeutic or prophylactic administration to a subject). It means to keep.

The synthesized compounds are separated from the reaction mixture and can also be purified by methods such as column chromatography, high pressure liquid chromatography or recrystallization. As will be appreciated by those skilled in the art, other methods of synthesizing the compounds of the formulas described herein are apparent to those of ordinary skill in the art. In addition, various synthetic steps may be performed in alternating order or order to obtain the desired compounds. Synthetic chemical modifications and protecting group methodologies (protected and unprotected) useful for the synthesis of the compounds described herein are known in the art and are described in, for example, R. Larock, Comprehensive Organic Transfomations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2rd. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); And L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and their later editions.

The term "subject" as used herein refers to an animal. Preferably the animal is a mammal. More preferably the mammal is a human. Subjects also include, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.

The compounds of the present invention can be modified by addition of appropriate functional groups to increase the selective biological properties. Such modifications are known in the art and can enhance biological penetration into a given biological system (e.g., blood, lymphatic, central nervous system), increase oral utility, increase solubility to allow injection by injection, and modify metabolism. And modifying the rate of secretion.

As used herein, the term "subject" means a mammal. Preferably the mammal is a human. Subjects also include, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.

As used herein, the term “pharmaceutically acceptable salts” is within the scope of the preferred medical opinion, and is suitable for use in contact with the skin of humans or lower animals without unexpected toxicity, inflammation, allergic reactions, and the like. Salts suitable for the sex / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, SM Berge et al. Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Science, 1977, 66, 1-19, incorporated herein by reference. Salts can be prepared in situ during the final separation or purification of the compounds of the invention, or independently by reacting the free base with a suitable organic acid. Pharmaceutically acceptable non-toxic acid addition salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfonic acid and perchloric acid, or acetic acid, oxalic acid, maleic acid, tartaric acid, Salts of amino groups formed with organic acids such as citric acid, succinic acid or malonic acid or using other methods known in the art such as ion exchange, including but not limited to. Other pharmaceutically acceptable salts are adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropio Nate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy Ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate , Palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, blood Acrylate, propionate, stearate, succinate, standing sulfate, tartrate, thiocyanate, p- toluenesulfonate, undead decanoate, balreo rate salts and include those similar to the one that is not limited to it. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Pharmaceutically acceptable salts are also suitable with non-toxic ammonium, quaternary ammonium and halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1 -C 6 sulfonates and aryl sulfonates Amine cations formed using the same counterion.

As used herein, the term "pharmaceutically acceptable ester" refers to an ester that is hydrolyzed in vivo and immediately degrades in the human body to be separated from the parent compound or salts thereof. Suitable ester groups are those derived from pharmaceutically acceptable aliphatic carboxylic acids, in particular alkanoic, alkenoic, cycloalkanoic and alkanedioic, in which each alkyl or alkenyl compound does not have at least 6 carbon atoms. Mountains include, but are not limited to. Particular esters include, but are not limited to, formate, acetate, propionate, butyrate, acrylate and ethyl succinate.

As used herein, the term “pharmaceutically acceptable prodrug” is within the scope of the preferred medical opinion and is suitable for use in contact with human or lower animal skin without unexpected toxicity, inflammation, allergic reactions, etc. As well as prodrugs of the compounds of the invention that are compatible with the benefit / risk ratio and effective for their intended purpose, it also refers to the zwitterion form of the compounds of the invention, if possible. The term "prodrug" refers to a compound that is rapidly modified in vivo to form the parent compound of the above structural formulas, such as, for example, hydrolyzed in blood. A detailed discussion can be found in T. Higuchi and V. Stella's Prodrugs as Novel delivery System, Vol. 14 of the A.C.S. Provided by the Symposium Series and Bioreversible Carriers in Drug Design (American Pharmaceutical Association and Pergamon Press, 1987) by Edward B. Roche, ed., Both books are incorporated herein by reference.

As used herein, the term "effective amount" or "therapeutically effective amount" means an amount that can inhibit HCV NS3 serine protease, thereby inhibiting the production of viral polyproteins essential for the replication of the virus. HCV serine protease inhibition envisioned by the present invention includes appropriate therapeutic and prophylactic regimens for a subject in need of such treatment. Treatment methods, dosages and requirements are selected from those known in the art in the possible methods and techniques. For example, the compounds of the present invention, in combination with pharmaceutically acceptable dosage excipients, are administered to a virus infected patient in an amount that is effective in alleviating the pain of the pharmaceutically acceptable method and virus infection. Alternatively, the compounds of the present invention can be used in vaccines or methods of protecting against HCV virus infection for extended periods of time. The compounds can be employed in a manner consistent with the conventional use of proteinase inhibitors in vaccines. For example, the compounds of the present invention may be combined with pharmaceutically acceptable excipients conventionally employed in vaccines, and may be administered in a prophylactically effective amount to protect against prolonged periods of HCV virus infection. Therefore, the protease inhibitor of the present invention can be administered to a subject as a drug to treat or prevent HCV virus infection.

Compounds of the invention can be modified by addition of appropriate functional groups to increase the selective biological properties. Such modifications are known in the art and can enhance biological penetration into a given biological system (e.g., blood, lymphatic, central nervous system), increase oral utility, increase solubility to allow injection by injection, and modify metabolism. And modifying the rate of secretion.

The compounds described herein have two or more asymmetric centers and as a result enantiomers, diastereomers, defined in isomeric terms (R)-or (S)-, or (D)-or (L)-of amino acids. And other stereoisomeric forms. The present invention includes all such possible isomers as well as their racemic and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the procedure described above or by dissolving racemic mixtures. Dissolution can be carried out in the presence of a solubilizer or by combining chromatography or repeated crystallization agents or such techniques known in the art. More details on dissolution can be found in Jacues et al., Enantiomers Racemates and Resolutions (John Wiley & Sons, 1981). If the compounds described herein have olefinic double bonds, or other geometrically asymmetric centers, and unless otherwise stated, the compounds include both E and Z geometric isomers. Similarly, all tautomeric forms are also included. Any arrangement of carbon-carbon double bonds shown herein is merely chosen for convenience and does not refer to a particular arrangement unless otherwise indicated; Therefore, the carbon-carbon double bonds optionally drawn here as trans may be cis, trans, or any proportion thereof.

Pharmaceutical composition

The pharmaceutical composition of the present invention consists of a therapeutically effective amount of a compound of the present invention formed with one or more pharmaceutically acceptable carriers. As used herein, the term “pharmaceutically acceptable carrier” refers to a nontoxic inert solid, semi-solid or liquid filler, diluent, encapsulated material or any type of adjuvant. Examples of substances which can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; Starches such as corn starch and potato starch; Cellulose and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragacanth rubber; malt; gelatin; Talc; Additives such as cocoa butter and suppository waxes; Oils such as peanut oil, cottonseed oil; Safflower oil; Sesame oil; olive oil; Corn oil and soybean oil; Glycols such as propylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Pyrogen-free water; Isotonic salts; Ringer's solution; In addition to ethyl alcohol and phosphate buffer solutions, non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and pigments, coatings, sweeteners, fragrances and flavors, preservatives and antioxidants may also be present in the compound. The pharmaceutical compositions of the present invention may be administered to humans or other animals by oral, rectal, extragastric, intravaginal, intraperitoneal, topical (as powder, ointment, or drop), oral or by spraying oral or nasal. .

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms are commonly used in the art, for example, water or other solvents, solubilizers and ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate , Propylene glycol, 1,3-butylene glycol, dimethyl 1-formamide, oils (especially cottonseeds, peanuts, corn, gums, olives, castors and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan Inert diluents such as thirty emulsifiers such as fatty acid esters and mixtures thereof. In addition to inert diluents, oral compounds may include wetting, emulsifying or suspending agents, sweetening agents, fragrances and flavorings as adjuvants.

Injectable formulations can be prepared, for example, by methods known in the art using sterile injectable aqueous solutions or oily suspensions using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in diluents or solvents, such as, for example, solutions in 1,3-butanediol, which are nontoxic and non-tolerant. Among the acceptable excipients and solvents that are applicable are water, Ringer's solution, U.S.P and isotonic sodium chloride solution. In addition, sterile, coagulated oils have traditionally been used as a solvent or suspending medium. For this purpose, any brand of solidified oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are also used in the preparation of injections.

Injectable formulations must be sterilized prior to use, for example by filtration through a bacterial retention filter or by binding to the bactericide in the form of sterile solid compounds that can be dissolved or dispersed in the bactericidal solution or as other sterile injectable mediators. .

To prolong the efficacy, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be done using liquid suspensions of crystalline or amorphous materials with poor solubility in water. The rate of absorption of the drug thus depends on the rate of dissolution which, in turn, depends on the size of the crystal and the form of the crystalline form. Alternatively, delayed absorption of the form of over-the-enterally administered drug is performed by dissolving or suspending the drug in an oil vehicle. Injectable storage forms are prepared by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide or polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer selected, the rate of drug release can be controlled. Examples of other biodegradable polymers are poly (orthoesters) and poly (anhydrides). Injectable storage forms can also be prepared by incorporating the drug into liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suitable non-irritating excipients, such as cocoa butter, polyethylene glycol or suppository waxes that are solid at room temperature but liquid at body temperature and melt in the rectum or vagina to release the active ingredient. Suppositories that can be prepared by mixing with a carrier.

Solid compositions of a similar type may be employed as fillers in soft, hard-filled gelatin capsules using excipients such as lactose or lactose, high molecular weight polyethylene glycols and the like.

The active compounds may also be in micro-encapsulated form with one or more additives as described above. Solid phase dosage forms of tablets, dragees, capsules, pills and granules can be prepared by coatings such as enteric coatings and shells, controlled release coatings and other coatings known in the pharmaceutical manufacturing art. In such solid dosage forms the active ingredient may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also conventionally include additional materials such as tablet lubricants and other tablet aids such as magnesium stearate, microcrystalline cellulose, in addition to inert diluents. For capsules, tablets and pills, the dosage form may also include a buffer. They may optionally contain an opaque agent and may be a composition which releases only the active ingredient (s) or, optionally, in certain parts of the intestine, optionally in a delayed manner. Examples of additional compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, plasters, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed in a sterile state with a pharmaceutically acceptable carrier and additionally necessary preservatives or buffers required. Ophthalmic forms, ear drops, eye drops, powders and solutions are also within the scope of the present invention. Ointments, plasters, creams and gels, together with the active ingredients of the present invention, include animal or vegetable fats, oils, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and It may contain additives such as zinc oxide or mixtures thereof.

Powders and sprays, in addition to the components of the present invention, may contain additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these materials. Sprays may additionally contain conventional compressed inert gases such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be achieved by dissolving or suspending the compound in the proper medium. Absorption accelerators may also be used to increase the flux of the compound to the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Antiviral activity

According to the treatment method of the present invention, a viral infection is treated in a subject such as a human or a lower mammal by administering to the subject an effective amount of a compound of the present invention in an amount necessary and the number of times necessary to achieve the desired result, or Prevented. As used herein, the term “effective amount of anti-hepatitis C virus” of a compound of the present invention is a sufficient amount of a compound that can reduce the activity of the virus in a subject and thus reduce the chronic hepatitis C virus symptoms of the aforementioned subject. Means. As is well known in the medical arts, the effective amount of a compound of the present invention against the anti-hepatitis C virus should be at a suitable benefit / risk ratio applicable to any medicinal treatment. As soon as the condition of the subject is improved, maintenance doses of the compounds, compositions, or binding compounds of the invention may be administered as needed. Subsequently, a single dose of administration, frequency of administration, or both, may be reduced if there is an improvement in symptoms up to the level at which the improved condition is maintained, and treatment may be discontinued when the symptoms are alleviated to the desired level. . However, subjects require long-term intermittent treatment based on the occurrence of disease symptoms.

However, it is obvious that the total daily dose of the compounds and compositions of the present invention should be determined by the attending physician within the scope of the desired medical judgment. The effective level of administration of a particular anti-hepatitis C virus to a particular patient may include the disorder treated and the extent of the disorder; The activity of the specific compound selected; The specific composition selected; The age, body weight, general health, sex and diet of the patient; time of administration, route of administration, secretion of the specific compound of choice; Duration of treatment; Compatibility with the drug or specific compound selected; And similar factors known in the pharmaceutical industry.

The total daily dose of a compound of the invention administered to a subject in single or divided doses is, for example, an amount of 0.01 to 50 mg / kg body weight or more typically 0.1 to 25 mg / kg body weight. Single dosage compositions may contain such amounts or amounts thereof in order to achieve a daily dosage. In general, the treatment regimen according to the present invention consists of administering from about 10 mg to about 1000 mg of a compound of the present invention in single or multiple doses to a patient in need of such treatment per day.

Abbreviations

Abbreviations used in the detailed description of schemes and examples are as follows.

ACN acetonitrile;

BME 2-mercaptoethanol;

BOP benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate;

COD cyclooctadiene;

DABCYL 6- (N-4′-carboxy-4- (dimethylamino) azobenzene) -aminohexyl-1-oxygen- (2-cyanoethyl)-(N, N-diisopropyl) -phosphoamidite;

DAST diethylaminosulfur trifluoride;

DCM dichloromethane;

DIAD diisopropyl azodicarboxylate;

DIBAL-H diisobutylaluminum hydride;

DIEA diisopropyl ethylamine;

DMAP N, N-dimethylaminopyridine;

DME ethylene glycol dimethyl ether;

Modified eagles media of DMEM Dulbecco;

DMF N, N-dimethyl formamide;

DMSO dimethyl sulfoxide;

DUPHOS

Figure 112005043726247-pct00470
;

EDANS 5- (2-Amino-ethylamino) -naphthalene-1-sulphonic acid;

EDCI or EDC 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride;

EtOAc ethyl acetate;

HATU oxygen (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate;

HMAB 4-hydroxymethylbenzoic acid AM resin;

Hoveyda's catalytic dichloro (o-isopropoxyphenylmethylene) (tricyclohexylphosphine) ruthenium (II);

KHMDS potassium bis (trimethylsilyl) amide;

Ms mesyl;

NMM N-4-methylmorpholine;

Ph phenyl;

PuPHOS

PyBrOP bromo-tri-pyrrolidino-phosphonium hexafluorophosphate;

RCM pulmonary metathesis reaction;

RT room temperature;

RT-PCR reverse transcriptase-polymerase chain reaction;

tBOC or Boc tert-butyloxy carbonyl;

TEA triethyl amine;

TFA trifluoroacetic acid;

THF tetrahydrofuran;

TLC thin layer chromatography;

TPP or PPh3 triphenylphosphine; And

Xantphos 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene.

Chemical structures with -NH or -OH groups here are represented without a hydrogen atom bonded to the depicted oxygen or nitrogen atoms. Therefore, where nitrogen or oxygen atoms in such structures appear to lack adequate valence, it means that such hydrogen atoms are present.

Synthesis Methods

The compounds and processes of the present invention will be described more clearly in connection with the following synthetic schemes detailing how the compounds of the present invention are prepared.

1. Substitution Method

The compounds of the present invention can generally be prepared through a substitution process which can be explained by the following scheme.

Figure 112005043726247-pct00471

Hydroxy proline or mesylated proline precursors can be used. This substitution method protocol is suitable for converting any hydroxy (or equivalent mesylate) proline compound or derived starting compound into a heterocyclic substituted proline derivative. Subsequent synthesis methods for the various procedures and intermediate product steps that can be used to prepare the compounds are described as follows.

A. Synthesis of hydroxy proline cyclic peptide precursors

Cyclic peptide precursors can be used to synthesize the compounds of the present invention. In some aspects, mesylides of cyclic precursors may be used.

In some aspects, commercially available Boc-hydroxyproline A

Figure 112005043726247-pct00472
Was treated with hydrochloric acid in dioxane to give the starting material Ib.

Cyclic  Synthesis of Peptide Precursors

Scheme  One

Figure 112005043726247-pct00473

The cyclic peptide precursor (Ig) is obtained via Boc-L-2-amino-8-nonenoic acid (Ia) and cis-L-hydroxyproline methyl ester via step AD generally described in Scheme 1. From Ib). For a more detailed description of the synthetic methodology used to generate the cyclic peptide precursor (Ig), see US Pat. No. 6,608,027, which is incorporated herein by reference in its entirety.

Macrocyclic  Of peptide precursors Mesylate  synthesis

Scheme  2

Figure 112005043726247-pct00474

Cyclic precursor mesylate was synthesized by forming a mesylate on the hydroxyl of the hydroxyl proline residue of the cyclic peptide precursor via the synthetic route generally described in Scheme 2 above.

Scheme  3

Figure 112005043726247-pct00475

The compounds of the present invention are 5-substituted-2H-, wherein the mesylate of macrocyclic peptide mesylate (IIa) is a representative synthesis of tetrazole as described in Scheme 5 below via the synthetic route generally described in Scheme 3. Prepared by substituting with tetrazole.

Scheme  4

Figure 112005043726247-pct00476

Compounds of the invention are prepared by replacing the mesylate of macrocyclic peptide mesylate (IIa) with 4,5-substituted-1H-triazole via the synthetic route generally described in Scheme 4. Representative synthesis of such triazoles is described in Scheme 6 below.

B. Synthesis of Substituents of W

W may be any of the substituents previously described herein. Synthesis of these various substituents is within the skill of one of ordinary skill in the art. Some exemplary syntheses are provided herein by way of example and no limitation. Other substituents are readily synthesized or marketed by those of ordinary skill in the art.

Tetrazole  synthesis

Structurally varying tetrazole (Va-Vq) was synthesized from commercial nitrile compounds as described in Scheme 5 below.

Scheme  5

Figure 112005043726247-pct00477

Those skilled in the art will recognize that various 5-substituted tetrazole compounds can be produced in this way with any nitrile containing compound suitable for the reaction conditions indicated above.

Triazole  synthesis

Scheme  6

Figure 112005043726247-pct00478

The triazoles of the present invention are formulated by reacting trimethylsilyl azide via the synthetic route generally described in Scheme 6 with the alkyne compound (VIa) made or marketed by the procedure described below. Commercially available alkynes suitable for triazole formation include, but are not limited to the following.

Figure 112005043726247-pct00479

Alkin Synthesis

Alkynes useful for the synthesis of triazoles can be made by any suitable method. The following are some representative syntheses.

Sonogashira ( Sonogashira ) reaction

Scheme  7

Figure 112005043726247-pct00480

Alkynes used in the present invention are primary alkyne compounds (VIIa), aryl halides (Y-halides) and triethyl in acetonitrile with PdCl 2 (PPh 3 ) 2 and CuI via the synthetic route generally described in Scheme 7. It can be made by Sonogashira reaction with an amine.

Commercially available aryl halides suitable for the Sonogashira reaction include, but are not limited to, the following compositions.

Figure 112005043726247-pct00481

Commercially available primary alkynes suitable for the Sonogashira reaction include, but are not limited to, the following compositions.

Figure 112005043726247-pct00482

Akynyl  Synthesis of Amide

Scheme  8

Figure 112005043726247-pct00483

Additional alkynes used in the present invention can be made by reacting alkynyl acid (Va), BOP and DIEA in DMF with amines (VIIb) via the synthetic route described generally in Scheme 8.

After substitution  transform

The resulting macrocyclic compound can be modified after W is attached. Some representative variations follow.

1. Synthesis of Phenolic Ester

Scheme  9

Figure 112005043726247-pct00484

Modifications after substitution of the macrocyclic compound (IIIa) to obtain various phenolic esters were carried out by the synthetic route generally described in Scheme 9.

2. Hydrolysis of Macrocyclic Peptide Ethyl Esters

Scheme  10

Figure 112006092596674-pct01028

Hydrolysis of the macrocyclic peptide ethyl esters of the invention is carried out by dissolving the macrocyclic peptide ethyl ester (IV) in dioxane and adding 1M LiOH via the synthetic route generally described in Scheme 10.

3. Use of Suzuki Coupling to Create More Bi-aryl Compounds

Scheme  11

Figure 112005043726247-pct00486

Compounds of the present invention are suzuki couples that add DME, aromatic boric acid, cesium carbonate and KF to bromine substituted triazole macrocyclic ethyl esters (see Example 26 for subsequent preparation) via the synthetic route generally described in Scheme 11. It can be further diversified by executing the ring.

II. Stepwise synthesis

The compounds of the present invention may also be formulated through stepwise synthesis rather than substitution mechanisms. The following is a typical synthesis in which W is tetrazole.

A. Synthesis of Proline Derivatives

Scheme  12

Figure 112005043726247-pct00487

B. Synthesis of Linear Tripeptide

Scheme  13

Figure 112005043726247-pct00488

Linear tripeptides containing tetrazol-substituted proline derivatives (XIIId) were prepared via the synthetic route described generally in Scheme 13.

C. Synthesis of Cyclic Peptides Through Ring-closing-Metathesis (RCM) Reaction

Scheme  14

Figure 112005043726247-pct00489

The formation of the macrocyclic compound (XIVb) was carried out using linear tripeptide (XIIId) via the RCM reaction generally described in Scheme 14.

D. Other Derivatives

1. The tetrazol substituted proline derivatives of the invention were synthesized by the synthetic route described generally in Scheme 12.

Scheme  15

Figure 112005043726247-pct00490

Additional tetrazol substituted proline derivatives of the invention were synthesized by the synthetic route described generally in Scheme 15.

2. Suzuki Coupling

Scheme  16

Figure 112005043726247-pct00491

Additional derivatives were formulated using the Suzuki coupling reaction generally described in Scheme 16.

III. Solid phase synthesis

Some compounds of the present invention are compatible with synthesis by solid phase synthesis. For example, triazole substituted proline derivatives (P2) can be synthesized and used in the on-resin assembly of linear tripeptide chains. Resin-bound tripeptides containing triazole-substituted proline derivatives provide cyclic tripeptides that are separated from the resin by hydrolysis to give a final product via a ring closure metathesis (RCM) reaction.

The following synthetic schemes represent the manner in which triazole substituted proline derivatives are made and the solid phase synthesis of the compounds of the present invention.

A. Synthesis of Proline Derivatives

Two methods are employed to synthesize the triazole substituted proline derivatives generally described by the schemes below.

1. Ring addition method

Scheme 17

Figure 112005043726247-pct00492

Ring addition methods to produce triazolyl proline derivatives involve the addition of 3 + 2 rings of azide proline derivatives (VIIa) and alkyne (VIIb) via the synthetic route generally described in Scheme 17. Representative synthesis of alkyne is described in Scheme 7 above.

2. Mesylate Method

Scheme  18

Figure 112005043726247-pct00493

Additional proline derivatives were synthesized through the substitution of mesylate (VIIa) with 4,5-substituted-1H-triazole via the synthetic route generally described in Scheme 18.

B. on-resin assembly and on-resin RCM

Scheme  19

Figure 112005043726247-pct00494

On resin assembly

On-resin assembly of linear peptide (VIId) followed by on-resin RCM was performed via steps A-D generally described in Scheme 19 to obtain a resin-bonded cyclic peptide precursor (VIIe).

Ⅳ. Other reactions

In some embodiments, substituent W is suitable for other kinds of reactions. For example, but not by way of limitation, when W is pyridazinone, the following reaction scheme is used. These methods can be used for other substituents, but are discussed here in the context of pyridazinone.

A condensation reaction

Scheme 20

Figure 112005043726247-pct00495

The simplest method shown in Scheme 20 utilizes Mitsunobu conditions followed by hydrolysis to LiOH to remove key intermediates (If) and commercially available pyridazinones (ⅩⅩa-1 to VIIa-4). It is condensation. More details on the Mitsunobu reaction can be found in O. Mitsunobu, Synthesis 1981, 1-28; D. L. Hughes, Org. React. 29, 1-162 (1983); D. L. Hughes, Organic Preparations and Procedures Int. 28, 127-164 (1996); and J. A. Dodge, S. A. Jones, Recent Res. Dev. Org. Chem. 1, 273-283 (1997).

Scheme  21

Figure 112005043726247-pct00496

A second method of preparing pyridazinone analogs of the present invention is to further manipulate the dibromine intermediate (XIa) chemically (Scheme 21). The standard Mitsunobu coupling of hydroxyl (If) and commercially available 4,5-dibrompyridazinone gave the desired macrocyclic XIa. Coupling of XIa with excess 3-thiophene bromic acid, cesium carbonate and potassium fluoride provided dithiophene (XIb). Hydrolysis of compounds XIa and XIb and LiOH gave the desired analogs XId and XIc, respectively. Many different bromic acids can be used in a similar manner to yield an excess of di-substituted pyridazinyl macrocyclic.

B. Bromide Differentiation

Scheme 22

Figure 112006092596674-pct01029

Differentiation between the bromide on macrocyclic VIIa is achieved through the addition of Michael. As shown in Scheme 22, commercially available pyrrolidine binds to dibromide to give compound XIIa in 87% yield. Some bromide adjacent to carbonyl produces an intermediate XIIb via Suzuki coupling with 3-thiophene bromic acid and is further treated with LiOH to give analog XIIc. A more detailed description of the Suzuki coupling reaction can be found in A. Suzuki, Pure Appl. Chem. 63, 419-422 (1991) and A. R. Martin, Y. Yang, Acta Chem. Scand. See 47, 221-230 (1993).

C. Sulfur containing nucleophiles

Scheme  23

Figure 112005043726247-pct00498

Although secondary amine nucleophilic pyrrolidines provide exclusive additions to the 5-bromide position on macrocyclic XIa, sulfur containing nucleophilic materials does not exhibit the same selectivity as shown in Scheme 23. With sulfur containing a nucleophilic substance, addition of both bromine phase of XIa is observed with the single bond product XIIIIa of mercaptopyrimidine with only one equivalent. The possibility of the separation of compounds XIIIa, XIIIB and starting material XIA by flash column chromatography suggests further Suzuki coupling of monoalkylated XIIIa with 3-thiophenic bromic acid followed by hydrolysis of XIIId with LiOH. To provide analog XIIIe. The di-alkylated product XIIIb is also hydrolyzed with LiOH to produce analog XIIIc.

D. Suzuki Coupling with Bromic Acid

Scheme 24

Figure 112006092596674-pct00499

With only a limited number of bromic acid available for Suzuki coupling, other coupling methods such as Still coupling and N-arylation reactions using Buchwald's chemistry were also investigated (Scheme 24). Coupling of the intermediate product VIa and 2-stanylcyazole to a Still standard condition followed by hydrolysis provided the analog IVa. With regard to the N-arylation reaction, the coupling of imidazole to dibromide XIa proceeded smoothly. Unfortunately, the hydrolysis to LiOH results in the substitution of the imidazole moiety on position 5 with methoxy (XIVb). A more detailed description of the Still coupling reaction can be found in JK Stille, Angew. Chem. Int. Ed. 25, 508-524 (1986); See M. Pereyre et al., Tin in Organic Synthesis (Butterworths, Boston, 1987) pp 185-207 passim., And TN Mitchell, Synthesis 1992, 803-815. A more detailed description of the Buchwald reaction can be found in JF Hartwig, Angew. Chem. Int. Ed. 37, 2046-2067 (1998).

delete

E. Other Diversified Pyridazinone Analogs

Scheme 25

Figure 112005043726247-pct00500

Another method for diversifying pyridazinone analogs is outlined in Scheme 25. As in the case of secondary amines, Michael addition of sodium azide, such as a nucleophilic atom, to dibromo produces only a single bonded compound XXVa. Suzuki coupling with 3-thiophene boronic acid also produces azide XXVb. Hydrolysis of compound XXVb yields analog XXVc. In addition, the azide moiety of compound XXVb is converted to tetrazole in standard state with sodium cyanide and hydrolysis is performed to give analog XXVd.

F. Synthesis of 5,6 pyridazinoyl macrocycles

Scheme 26

Figure 112005043726247-pct00501

The synthesis of the 5,6 pyridazinoneyl macrocycle XXVIb is outlined in scheme 26. Commercially available 5-bromo-6-phenyl-2H-pyridazin-3-one is condensed with the core intermediate product via Mitsunobu conditions to prepare compound XXVIa. Product XXVIa is subjected to Suzuki coupling conditions with 3-thiophene boronic acid and hydrolysis is performed to produce the desired analog XXVIb.

The compounds and processes of the present invention will be more readily understood in connection with the following examples, which are merely illustrative and are not intended to limit the scope of the invention. Various modifications and variations of the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those related to the chemical structures, substituents, derivatives, formulas and / or methods of the invention, may be made without departing from the spirit and claims of the invention.

Example 1. Synthesis of the cyclic peptide precursor

Figure 112005043726247-pct00502

1A. To a solution of commercial cis-L-hydroxyproline methyl ester (1b) (1.09 g, 6 mmol) and Boc-L-2-amino-8-nonenoic acid (1a) (1.36 g, 5 mol) in 15 ml DMF. DIEA (4 ml, 4 eq.) And HATU (4 g, 2 eq.) Are added. Bonding is performed at 0 ° C. over 1 hour. The reaction mixture is diluted with 100 ml EtOAc and washed with 2 × 20 ml 5% citric acid, 2 × 20 ml water, 4 × 20 ml 1M NaHCO 3 and 2 × 10 ml brine, respectively. The organic phase is dried over anhydrous Na 2 SO 4 and then evaporated, identified by HPLC (retention time = 8.9 min, 30-70%, 90% B) and MS (found 421.37, M + Na +). Dipeptide 1c (1.91 g, 95.8%).

1B. Dipeptide (1c) (1.91 g) is dissolved in 15 mL of dioxane and 15 mL of 1N LiOH aqueous solution, and the hydrolysis reaction is carried out at room temperature for 4 hours. The reaction mixture is oxidized with 5% citric acid and extracted with 100 mL EtOAc, washed with 2x20 ml of water, 2x20 ml of 1M NaHCO 3 and 2x20 ml of brine, respectively. The organic phase is dried over anhydrous Na 2 SO 4 and then removed in vacuo to produce free carboxylic acid compound (1d) (1.79 g, 97%) used in the next step synthesis without the need for further purification.

1C. To a solution of free acid (1.77 g, 4.64 mmol) in the stomach in 5 ml DMF, D-β-vinyl cyclopropane amino acid ethyl ester (1e) (0.95 g, 5 mmol), DIEA (4 ml, 4eq.) And HATU (4 g, 2eq) ) Is added. Bonding is performed at 0 ° C. over 5 hours. The reaction mixture is diluted with 80 mL EtOAc and washed with 2 × 20 ml 5% citric acid, 2 × 20 ml water, 4 × 20 ml 1M NaHCO 3 and 2 × 10 ml brine, respectively. The organic phase is dried over anhydrous Na 2 SO 4 and then evaporated. The residue is purified by silica gel flash chromatography using different ratios of hexanes: EtOAc as eluent phase (5: 1 → 3: 1 → 1: 1 → 1: 2 → 1: 5). The linear tripeptide (1f) is isolated as an oil after removal of the eluent (1.59 g, 65.4%) and identified by HPLC (retention time = 11.43 min) and MS (found 544.84, M + Na +).

1D. Lung Regeneration (RCM). A solution of linear tripeptide (1f) (1.51 g, 2.89 mmol) in 200 ml dry DCM is deoxygenated by bubbling N 2 . Hoveyda's first production catalyst (5 mol% eq.) Is then added as a solid. The reaction is refluxed for 12 hours under N 2 environment. The solvent is evaporated and the residue is subjected to silica gel flash chromatography using different ratios of hexanes: EtOAc as eluent phase (9: 1 → 5: 1 → 3: 1 → 1: 1 → 1: 2 → 1: 5). Is purified. The cyclic peptide precursor (1) is isolated as a white powder after removal of the eluting solvent (1.24 g, 87%), HPLC (retention time = 7.84 min, 30-70%, 90% B) and MS (found 516.28, M). + Na +). For a more detailed description of the synthetic methods employed to generate the cyclic peptide precursor 1, see US Pat. No. 6,608,027, incorporated herein by reference.

Example 2. Synthesis of the cyclic peptide precursor mesylate

Figure 112005043726247-pct00503

2A. To a solution of DIEA (0.4 ml, 2 mmol) and macrocyclic peptide precursor (1) (500 mg, 1.01 mmol) in 2.0 ml DCM, mesylate chloride (0.1 ml) was added slowly at 0 ° C. where the reaction was maintained for 3 hours. . 30 mL EtOAc was then added and washed with 2 × 20 ml 5% citric acid, 2 × 20 ml water, 2 × 20 ml 1M NaHCO 3 and 2 × 10 ml brine, respectively. The organic phase is dried over anhydrous Na 2 S0 4 and evaporated to produce the title compound mesylate, which is used in the next step synthesis without further purification.

Example 3. Tetrazol Synthesis

For use in preparing the tetrazolyl macrocycle of the invention, structurally different kinds of tetrazol IIIa-IIIq are synthesized from commercially available nitrile compounds as described below:

Figure 112005043726247-pct00504

3-Cl-4-hydroxybenzoacetonitrile (0.31 g, 5 mol), NaN 3 (0.65 g, 10 mmol) and triethylamine hydrochloric acid (0.52 g, 3 mmol) were added to a sealed tube containing 5 ml xylene. The mixture was stirred vigorously at 140 ° C. over 20-30 hours. The reaction mixture is then cooled and poured into a mixture of EtOAc (30 ml) and aqueous citric acid solution (20 mL). After washing with 2 × 10 ml of water and 2 × 10 ml of brine, the organic phase is dried over anhydrous Na 2 SO 4 and evaporated to a yellow solid. After recrystallization with EtOAc-hexane, tetrazole compound 3a was obtained in good yield (0.4 g, 86%), high purity (> 90%, by HPLC), NMR and MS (found 197.35 and 199.38, M). + H +).

Example 4. A compound of formula II wherein A = tBOC , G = OH, L = absent ,

W is

Figure 112005043726247-pct00505
, Q = absent, Y = phenyl , j = 3, m = s = 1, and R3 = R4 = H

Proline derivative synthesis

Figure 112005043726247-pct00506

3.85 dropwise in a solution of N, N-diisopropylethyl amine (DIEA, 12 mL, 60 mmol) and N-Boc-cis-hydroxyproline methyl ester (4a) (10 g, 40.8 mmol) in 110 mL DCM. mL of mesylate chloride (50 mmol) was added and the resulting reaction mixture was stirred at 0 ° C. for 3 hours. TLC (hexane: ethyl acetate = 1: 1, v / v) shows that Boc-cis-Hyp-OMe (4a) is converted to its mesylate (4b) as a whole. After the reaction is considered complete by TLC, the reaction mixture is diluted with 100 ml EtOAc, washed with 2 x 50 ml of 5% citric acid and 2 x 30 ml brine and dried over anhydrous Na 2 SO 4 . Removal of the solvent provides 13 g (98% yield) N-Boc-cis-4-mesylate-proline methyl ester (4b) used in step (B) without further purification.

To a solution of mesylate (4b) (0.65 g, 2 mmol) in 5 mL DMF is added 4 mmol of 5-phenyl-1H-tetrazole and anhydrous sodium carbonate (0.53 g, 5 mmol). The resulting reaction mixture was stirred vigorously at 60 ° C. for 6-12 hours. TLC (hexane: ethylacetate = 1: 1, v / v) showed that mesylate (4b) was completely converted to trans 4-tetrazol-substituted proline derivative (4c). After the reaction is considered complete by TLC, the reaction mixture is diluted with 30 ml EtOAc and washed with 1M Na 2 CO 3 (3 × 10 ml), water (3 × 10 ml), 5% citric acid (3 × 10 ml) and brine (3 × 10 ml), respectively. The organic phase is dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give 5-phenyl tetrazol substituted proline derivative (4c) in excellent yield (94%) and high purity (> 90%). 4c: 94% yield, [M + Nz] + = 396.39

Synthesis of Linear Tripeptide

Figure 112005043726247-pct00507

A. (1) Dipeptide (4e) is 0.22 g (0.6 mmol) of N-Boc-trans-4- (3-phenyl tetrazolyl) -proline methyl ester (4c) in 6 mL of dioxane and 2 mL of 1N LiOH aqueous. It is prepared by dissolving in solution. The resulting reaction mixture is stirred for 3-8 hours at RT to allow hydrolysis of the methyl ester. The reaction mixture is oxidized with 5% citric acid, taken out with 40 mL EtOAc and washed with 2x20ml of water, 2x20ml of 1M NaHCO 3 and 2x10ml of brine, respectively. The organic phase is dried over anhydrous Na 2 SO 4 , concentrated in vacuo, and produces free carboxylic acids, which are used in the next step synthesis without the need for further purification. (2) To a cooled (0 ° C.) solution of free acid (0.20 g, 0.55 mmol) obtained above in 2 ml DMF, D-β-vinyl cyclopropane amino acid ethyl ester (4d) (0.1 g, 0.52 mmol), DIEA ( 0.4 ml, 4eq.) And HATU (O.4g, 2eq) are added. The resulting reaction mixture was stirred at 0 ° C. for 0.5-3 hours. The reaction mixture is diluted with 40 mL EtOAc and washed with 2 × 20 ml of 5% citric acid, 2 × 20 ml of water, 4 × 20 ml of 1M NaHCO 3 and 2 × 10 ml brine, respectively. The organic phase was dried over anhydrous Na 2 SO 4 , concentrated in vacuo, fed dipeptide (4e) (0.24 g, 94%), HPLC (retention time = 10.03 min) and MS (found 519.22, M + Na +) Is identified by.

B. (1) Tripeptide (4 g) is prepared by deprotecting an amine of dipeptide 4e (2.24 g, 0.49 mmol) in 2 mL TFA at 0 ° C. for 10 min. After removal of TFA in vacuo, the free amine product is directly followed by the binding reaction. (2) To a cooled (0 ° C.) solution of the free amine compound obtained above in 2 ml DMF, Boc-2-amino-8-nonenoic acid (4f) (0.136 g, 0.50 mmol), DIEA (0.4 ml, 4eq) .) And HATU (O.4g, 2eq) are added. Bonding is performed at 0 ° C. for 0.5-3 hours. The reaction mixture is diluted with 40 mL EtOAc and washed with 2 × 20 ml of 5% citric acid, 2 × 20 ml of water, 4 × 20 ml of 1M NaHCO 3 and 2 × 10 ml brine, respectively. The organic phase was dried over anhydrous Na 2 S0 4 and concentrated in vacuo, tripeptide (4 g) (0.28 g, identified for 2 steps) by HPLC (detention time = 14.03 min) and MS (found 672.30, M + Na +). 88%).

Synthesis of Cyclic Peptides Through Pulmonary Cyclolysis (RCM)

Figure 112005043726247-pct00508

A. A solution of linear tripeptide (4 g) (71 mg, 0.109 mmol) in 50 ml dry DCM is deoxygenated by bubbling N 2 . To the resulting degassed solution, Cathode's Cat. (5-10 mol% eq.) Is added as a solid and the resulting reaction mixture is refluxed under N 2 over 5-20 hours. The reaction mixture is then concentrated in vacuo and the residue is silica gel flash chromatography using different ratios of hexanes: EtOAc as the eluting phase (9: 1 → 5: 1 → 3: 1 → 1: 1 → 1: 2). It is purified by chromatography. The macrocyclic peptide (4i) was isolated as a white powder by evaporation of an eluting solvent (58 mg, 85.5%), HPLC (retention time = 11.80 min, 30-80%, 90% B), and MS (found 644.66, M + Na +).

B. Hydrolysis of Ethyl Ester

The title compound is prepared by dissolving Compound (4i) (20 mg) in 2 mL of dioxane and 1 mL of 1N LiOH aqueous solution. The resulting reaction mixture was stirred for 4-8 hours at RT. The reaction mixture is then oxidized with 5% citric acid, taken out with 10 mL EtOAc and washed with 2x20 ml of water. The solvent is evaporated and the residue is purified over 20 minutes by HPLC on a YMC AQ12S11-0520WT column with a 30-80% (100% acetonitrile) gradient. After lyophilization, the title compound is obtained as a white amorphous solid.

[M + Na] + = 616.72

Example 5. A compound of formula II wherein A = tBOC , G = OH, L = absent ,

W =

Figure 112005043726247-pct00509

Q = absent, Y = 2- Bromophenyl , j = 3, m = s = 1, and R3 = R4 = H

5A. Proline derivative synthesis

The proline derivatives of this example are prepared by the procedure shown in Example 4 (I) with 5- (2-bromophenyl) -1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester (4a).

[M + Na] + = 396.39

5B. Synthesis of Linear Tripeptide

The linear peptide of this example is a proline derivative prepared in step (5A), D-β-vinyl-cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid. It is prepared through the procedure shown in II).

[M + H] + = 728.41

5C. Lung Regeneration

The macrocyclic peptide ethyl ester of this example is prepared as the linear peptide of step (5B) through the procedure shown in Example 4 (III).

[M + Na] + = 722.37

5D. Hydrolysis of Ethyl Ester

The title compound is ultimately obtained through the hydrolysis described in Example 4 (IV) from the ethyl ester of step (5C).

[M + H] + = 672.49

Example 6 Compounds of Formula II wherein A = tBOC , G = OH, L = absence,

W =

Figure 112005043726247-pct00510

Q = absent, Y = 3- Bromophenyl , j = 3, m = s = 1, and R3 = R4 = H

6A. Proline derivative synthesis

The proline derivatives of this example are prepared by the procedure shown in Example 4 (I) with 5- (3-bromophenyl) -1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester (4a).

[M + Na] + = 396.39

6B. Synthesis of Linear Tripeptide

The linear peptide of this example is the proline derivative prepared in step (6A), D-β-vinyl-cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid, the procedure shown in Example 4 (II). Be prepared through.

[M + H] + = 728.41

6C. Lung Regeneration

The macrocyclic peptide ethyl ester of this example is prepared as the linear peptide of step (6B) through the procedure shown in Example 4 (III).

[M + Na] + = 722.37

6D. Hydrolysis of Ethyl Ester

The title compound is ultimately obtained through the hydrolysis described in Example 4 (IV) from the ethyl ester of step (6C).

[M + H] + = 672.49

Example 7. A compound of formula II wherein A = tBOC , G = OH, L = absent ,

W =

Figure 112005043726247-pct00511

Q = absent, Y = 4- Bromophenyl , j = 3, m = s = 1, and R3 = R4 = H

7A. Proline derivative synthesis

The proline derivatives of this example are prepared by the procedure shown in Example 4 (I) with 5- (4-bromophenyl) -1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester (4a).

[M + Na] + = 396.39

7B. Synthesis of Linear Tripeptide

The linear peptides of this example were the proline derivatives prepared in step 7A, D-β-vinyl-cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid, as shown in Example 4 (II). Be prepared through the procedure.

[[M + Na] + H] + = 728.41

7C. Lung Regeneration

The macrocyclic peptide ethyl ester of this example is prepared as the linear peptide of step (7B) through the procedure shown in Example 4 (III).

[M + Na] + = 722.37

7D. Hydrolysis of Ethyl Ester

The title compound is ultimately obtained via the hydrolysis described in Example 4 (IV) from the ethyl ester of step (7C).

[M + H] + = 672.49

Example 8. A compound of formula II wherein A = tBOC , G = OH, L = absent ,

W =

Figure 112005043726247-pct00512

Q = absent, Y = 5- Bromo -2- Thienyl , j = 3, m = s = 1, and R3 = R4 = H

8A. Proline derivative synthesis

The proline derivative of this example was prepared by the procedure shown in Example 4 (I) with 5- (5-bromo-2-thienyl) -1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester (4a). do.

[M + Na] + = 480.23

8B. Synthesis of Linear Tripeptide

The linear peptide of this example is the proline derivative prepared in step (8A), D-β-vinyl-cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid, following the procedure shown in Example 4 (II). Be prepared through.

[M-Boc + H] + = 634.29

8C. Lung Regeneration

The macrocyclic peptide ethyl ester of this example is prepared as the linear peptide of step (8B) through the procedure shown in Example 4 (III).

[M + Na] + = 736.21

8D. Hydrolysis of Ethyl Ester

The title component is ultimately obtained via the hydrolysis described in Example 4 (IV) from the ethyl ester of step (8C).

[M + H] + = 678.22

Example 9. A compound of formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00513

Q = absent, Y = 2- Bromo -4- Pyridyl , j = 3, m = s = 1, and R3 = R4 = H

9A. Proline derivative synthesis

The proline derivative of this example was prepared by the procedure shown in Example 4 (I) with 5- (2-bromo-4-pyridyl) -1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester (4a). do.

[M + Na] + = 453.23

9B. Synthesis of Linear Tripeptide

The linear peptide of this example is the proline derivative prepared in step (9A), D-β-vinyl-cyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonenoic acid, following the procedure shown in Example 4 (II). Be prepared through.

[M-Boc + H] + = 629.31

9C. Lung Regeneration

The macrocyclic peptide ethyl ester of this example is prepared as the linear peptide of step (9B) through the procedure shown in Example 4 (III).

[M + Na] + = 723.36

9D. Hydrolysis of Ethyl Ester

The title component is ultimately obtained through the hydrolysis described in Example 4 (IV) from the ethyl ester of step (9C).

[M + H] + = 673.26

Example 10. A compound of formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00514

Q = absent, Y = 2-biphenyl, j = 3, m = s = 1, and R3 = R4 = H

Pd (PPh 3 ) to an oxygen-depleted solution of ethyl ester component (40 mg), phenylboronic acid (10 mg), KF (100 mg) and Cs 2 CO 3 (80 mg) from step (5C) obtained above in 5 ml DME. 4 ) (5 mg) is added in solid form. The resulting reaction mixture was heated to 90 ° C. in an oil bath and stirred vigorously for 6-12 hours. The solvent is evaporated and the residue is purified by silica gel flash chromatography using different ratios of hexanes: EtOAc as eluent phase (9: 1 → 5: 1 → 3: 1 → 1: 1 → 2: 1). The macrocyclic bi-aryl peptide ethyl ester is then separated into white powder by evaporation of the directly hydrolyzed eluent (31 mg, 78%) as previously described in Example 4 (IV), Purification by HPLC.

[M + Na] + = 692.38

Example 11. A compound of formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00515

Q = absent, Y = 3-biphenyl, j = 3, m = s = 1, and R3 = R4 = H

The title compound is prepared with phenylboronic acid through the procedure shown in Example 10 and the ethyl ester compound from step (6C), and hydrolysis of the ethyl ester is carried out according to the procedure of Example 4 (IV).

[M + Na] + = 692.38

Example 12. A compound of formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00516

Q = absent, Y = 4-biphenyl, j = 3, m = s = 1, and R3 = R4 = H

The title compound is prepared with phenylboronic acid through the procedure shown in Example 10 and the ethyl ester compound from step (7C), and hydrolysis of the ethyl ester is carried out according to the procedure of Example 4 (IV).

[M + Na] + = 692.38

Example 13. A compound of formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00517

Q = absent, Y = 3- (3- Thienyl ) Phenyl , j = 3, m = s = 1, and R3 = R4 = H

The title compound is prepared with 3-thienylboronic acid through the procedure shown in Example 10 and the ethyl ester compound from step (6C), and hydrolysis of the ethyl ester is carried out according to the procedure of Example 4 (IV).

[M + Na] + = 698.32

Example 14. A compound of formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00518

Q = absent, Y = 3- (p- Trifluoromethoxyphenyl ) Phenyl , j = 3, m = s = 1, and R3 = R4 = H

The title compound was prepared with p-trifluoromethoxyphenylboronic acid through the procedure shown in Example 10 and ethyl ester compound from step (6C), and hydrolysis of ethyl ester according to the procedure of Example 4 (IV). Is performed.

[M + Na] + = 776.35

Example 15. A compound of formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00519

Q = absent, Y = 3- (p- Cyanophenyl ) Phenyl , j = 3, m = s = 1, and R3 = R4 = H

The title compound is prepared with p-cyanophenylboronic acid through the procedure shown in Example 10 and the ethyl ester compound from step (6C), followed by hydrolysis of the ethyl ester according to the procedure of Example 4 (IV). .

[M + Na] + = 692.38

Example 16. A compound of formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00520

Q = absent, Y = 4- (3- Thienyl ) Phenyl , j = 3, m = s = 1, and R3 = R4 = H

The title compound is prepared with 3-thienylboronic acid through the procedure shown in Example 10 and the ethyl ester compound from step (7C), and hydrolysis of the ethyl ester is carried out according to the procedure of Example 4 (IV).

[M + Na] + = 698.32

Example 17. A compound of formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00521

Q = absent, Y = 4- (p- Trifluoromethoxyphenyl ) Phenyl , j = 3, m = s = 1, and R3 = R4 = H

The title compound was prepared with ethyl ester compound from step (7C) and p-trifluoromethoxyphenylboronic acid via the procedure shown in Example 10, and hydrolysis of ethyl ester according to the procedure of Example 4 (IV). Is performed.

[M + Na] + = 776.35

Example 18. A compound of formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00522

Q = absent, Y = 4- (p- Cyanophenyl ) Phenyl , j = 3, m = s = 1, and R3 = R4 = H

The title compound is prepared with ethyl ester compound from step (7C) and p-cyanophenylboronic acid via the procedure shown in Example 10, and hydrolysis of the ethyl ester is carried out according to the procedure of Example 4 (IV). .

[M + Na] + = 692.38

Example 19. A compound of formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00523

Q = absent, Y = 5- Phenyl -2- Thienyl , j = 3, m = s = 1, and R3 = R4 = H

The title compound is prepared with ethyl ester compound from step (8C) and phenylboronic acid via the procedure shown in Example 10, and hydrolysis of the ethyl ester is carried out according to the procedure of Example 4 (IV).

[M + Na] + = 698.32

Example 20. A compound of formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00524

Q = absent, Y = 5- Phenyl -3- Pyridyl , j = 3, m = s = 1, and R3 = R4 = H

The title compound is prepared with ethyl ester compound from step (9C) and phenylboronic acid via the procedure shown in Example 10, and hydrolysis of the ethyl ester is carried out according to the procedure of Example 4 (IV).

[M + Na] + = 708.30

Example 21. A compound of formula II wherein A = tBOC, G = OEt, L = absent,

W =

Figure 112005043726247-pct00525

Q = absent, Y = 3- Chloro -4- Hydroxyphenyl , j = 3, m = s = 1, and R3 = R4 = H

Substitution method

The title compound is prepared via substitution of mesylate (2) and tetrazole (3a). The substitution method is carried out by dissolving 0.041 mmol of macrocyclic peptide precursor mesylate (2) and 0.123 mmol of tetrazole (3a) in 3 ml of DMF and adding 0.246 mmol of sodium carbonate (60 mg). The resulting reaction mixture was stirred at 60 ° C. for 4-6 hours, then cooled and extracted with ethyl acetate. The organic extract is washed with water (2x30 ml) and the organic solution is concentrated in vacuo to be used as a crude form for the hydrolysis of ethyl esters.

Example 22. A compound of Formula II wherein A = tBOC , G = OH, L = absent , W is

Figure 112005043726247-pct00526
, Q is absent, Y = 3 -chloro- 4 -hydroxyphenyl , j = 3, m = s = 1, and R 3 = R 4 = H.

This title compound was prepared by dissolving the compound of Example 4 (20 mg) in 2 mL of dioxane and 1 mL of 1N LiOH aqueous solution. The resulting reaction mixture was stirred for 4-8 hours at room temperature. The reaction mixture was acidified with 5% citric acid, extracted with 10 mL of EtOAc and washed with 2 * 20 ml of water. The solvent was evaporated and the residue was purified by HPLC on a YMC AQ12S110 520WT column for 20 minutes with 100% acetonitrile 30 to 80% gradient. After freeze vacuum drying, the title compound was obtained as an amorphous white solid.

[M + Na] + = 666.24.

Example 23. A compound of Formula II wherein A = tBOC , G = OH, L = absent , W

Figure 112005043726247-pct00527
, Q is absent, Y = 3- bromo- 4 -hydroxyphenyl , j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the method of substitution described in Example 21 with mesylate 2 and tetrazole 3b from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 712.18.

Example 24. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00528
, Q is absent, Y = 2-methyl-4-bromophenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 with mesylate 2 and tetrazole 3c from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 708.30.

Example 25. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00529
, Q is absent, Y = 3-methyl-4-bromophenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the method of substitution described in Example 21 by mesylate 2 and tetrazole 3d from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 708.30.

Example 26. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00530
, Q is absent, Y = n-propyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the method of substitution described in Example 21 by mesylate 2 and tetrazole 3e from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 582.33.

Example 27. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00531
, Q is absent, Y = n-butyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the substitution method described in Example 21 by mesylate 2 and tetrazole 3f from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 596.36.

Example 28. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00532
, Q is absent, Y = 4-ethoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 by Mesylate 2 and Tetrazol 3g from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 660.92.

Example 29. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00533
, Q is absent, Y = 4-propoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 with mesylate 2 and tetrazole 3h from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 674.29.

Example 30. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00534
, Q is absent, Y = 4-butoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the method of substitution described in Example 21 by mesylate 2 and tetrazole 3i from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 688.32.

Example 31. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00535
, Q is absent, Y = 3-methoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the method of substitution described in Example 21 by mesylate 2 and tetrazole 3j from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 646.92.

Example 32. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00536
, Q is absent, Y = 3,4-dimethoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution process described in Example 21 with mesylate 2 and tetrazole 3k from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 676.38.

Example 33. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00537
, Q is absent, Y = 4-methoxy-1-naphthyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the substitution method described in Example 21 with mesylate 2 and tetrazole 3l from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 697.00.

Example 34. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00538
, Q is absent, Y = 4-phenoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 with mesylate 2 and tetrazol 3m from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 708.51.

Example 35. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00539
, Q is absent, Y = benzyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the substitution method described in Example 21 with mesylate 2 and tetrazole 3n from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 630.35.

Example 36. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00540
, Q is absent, Y = p-phenylbenzyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the method of substitution described in Example 21 with mesylate 2 and tetrazole 3o from Example 3, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 706.38.

Example 37. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00541
, Q is absent, Y = 3-chlorophenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 by mesylate 2 and 5- (3-chlorophenyl) -1H-tetrazole from Example 3, followed by ethyl ester by the procedure of Example 22. Hydrolysis was carried out.

[M + Na] + = 650.33.

Example 38. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00542
, Q is absent, Y = 3-fluorophenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the substitution method described in Example 21 by mesylate 2 and 5- (3-fluorophenyl) -1H-tetrazole from Example 3, followed by ethyl by the procedure of Example 22. Hydrolysis of the ester was performed.

[M + Na] + = 634.37.

Example 39. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00543
, Q is absent, Y = methoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 by mesylate 2 and 5- (3-methoxyphenyl) -1H-tetrazole from Example 3, followed by ethyl by the procedure of Example 22. Hydrolysis of the ester was performed.

[M + Na] + = 646.92.

Example 40. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00544
, Q is absent, Y = 3-phenoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 by mesylate 2 and 5- (3-phenoxyphenyl) -1H-tetrazole from Example 3, followed by ethyl by the procedure of Example 22. Hydrolysis of the ester was performed.

[M + Na] + = 708.51.

Example 41. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00545
, Q is absent, Y = benzyloxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 by mesylate 2 and 5- (3-benzyloxyphenyl) -1H-tetrazole from Example 3, followed by ethyl by the procedure of Example 22. Hydrolysis of the ester was performed.

[M + Na] + = 722.32.

Example 42. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00546
, Q is absent, Y = 3-trifluoromethylphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 by mesylate 2 and 5- (3-trifluoromethylphenyl) 1H-tetrazole from Example 3, followed by ethyl ester by the procedure of Example 22 Hydrolysis was carried out.

[M + Na] + = 684.32.

Example 43. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00547
, Q is absent, Y = 4-bromophenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the substitution method described in Example 21 by mesylate 2 and 5- (4-bromophenyl) -1H-tetrazole from Example 3, followed by ethyl by the procedure of Example 22. Hydrolysis of the ester was performed.

[M + Na] + = 696.28.

Example 44. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00548
, Q is absent, Y = 4-fluorophenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the substitution method described in Example 21 with mesylate 2 and 5- (4-fluorophenyl) -1H-tetrazole from Example 3, followed by ethyl by the procedure of Example 22. Hydrolysis of the ester was performed.

[M + Na] + = 634.36.

Example 45. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00549
, Q is absent, Y = 4-methoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the substitution method described in Example 21 by mesylate 2 and 5- (4-methoxyphenyl) -1H-tetrazole from Example 3, followed by ethyl by the procedure of Example 22. Hydrolysis of the ester was performed.

[M + Na] + = 646.36.

Example 46. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00550
, Q is absent, Y = 4-ethoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the substitution method described in Example 21 by mesylate 2 and 5- (4-ethoxyphenyl) -1H-tetrazole from Example 3, followed by ethyl by the procedure of Example 22. Hydrolysis of the ester was performed.

[M + Na] + = 660.92.

Example 47. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00551
, Q is absent, Y = 4-trifluoromethylphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the substitution method described in Example 21 with mesylate 2 and 5- (4-trifluoromethylphenyl) -1H-tetrazole from Example 3, followed by the procedure of Example 22 Hydrolysis of ethyl ester was performed.

[M + Na] + = 684.32.

Example 48. A compound of Formula II, wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00552
, Q is absent, Y = 3,5-di (trifluoromethyl) phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 with mesylate 2 and 5- (3,5-di (trifluoromethyl) phenyl) -1H-tetrazole from Example 3, followed by Hydrolysis of the ethyl ester was performed by the procedure of Example 22.

[M + Na] + = 766.32.

Example 49. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00553
, Q is absent, Y = 4- (N, N-dimethylamino) -3,5-di (trifluoromethyl) phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared in Example 21 by mesylate 2 and 5- ( 4- (N, N-dimethylamino) -3,5-di (trifluoromethyl) phenyl ) -1H-tetrazole from Example 3. Prepared via the substitution method described, followed by hydrolysis of the ethyl ester by the procedure of Example 22.

[M + Na] + = 695.39.

Example 50. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00554
, Q is absent, Y = 2,4-dichlorophenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the substitution method described in Example 21 with mesylate 2 and 5- ( 2,4-dichlorophenyl ) -1H-tetrazole from Example 3, followed by the procedure of Example 22 Hydrolysis of ethyl ester was performed.

[M + Na] + = 684.27.

Example 51. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00555
, Q is absent, Y = 3,5-dichlorophenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the substitution method described in Example 21 with mesylate 2 and 5- ( 3,5-dichlorophenyl ) -1H-tetrazole from Example 3, followed by the procedure of Example 22 Hydrolysis of ethyl ester was performed.

[M + Na] + = 684.27.

Example 52. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00556
, Q is absent, Y = 3,4-dichlorophenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the substitution method described in Example 21 with mesylate 2 and 5- ( 3,4-dichlorophenyl ) -1H-tetrazole from Example 3, followed by the procedure of Example 22 Hydrolysis of ethyl ester was performed.

[M + Na] + = 684.27.

Example 53. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00557
, Q is absent, Y = 2-pyridyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 by mesylate 2 and 5- (2-pyridyl) -1H-tetrazole from Example 3, followed by ethyl ester by the procedure of Example 22. Hydrolysis was carried out.

[M + Na] + = 617.60.

Example 54. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00558
, Q is absent, Y = 2-pyridyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 by mesylate 2 and 5- (2-pyridyl) -1H-tetrazole from Example 3, followed by ethyl ester by the procedure of Example 22. Hydrolysis was carried out.

[M + Na] + = 617.60.

Example 55. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00559
, Q is absent, Y = 3-pyridyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 with mesylate 2 and 5- (3-pyridyl) -1H-tetrazole from Example 3, followed by ethyl ester by the procedure of Example 22 Hydrolysis was carried out.

[M + Na] + = 645.24.

Example 56. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00560
, Q is absent, Y = 4-pyridyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared via the substitution method described in Example 21 by mesylate 2 and 5- (4-pyridyl) -1H-tetrazole from Example 3, followed by ethyl ester by the procedure of Example 22. Hydrolysis was carried out.

[M + Na] + = 595.50.

Example 57. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00561
, Q is absent, Y = 4-methoxy-3-bromophenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

57A. Tetrazole formation

The tetrazole of this example was prepared by dissolving 3-bromo-4-hydroxy-benzonitrile in DMF solvent, methyl iodide, and stirring at room temperature for 3 to 12 hours. The resulting reaction mixture was diluted with EtOAc and washed with water and brine. The resulting organic phase was dried over Na 2 SO 4 and concentrated in vacuo to yield 3-bromo-4-methoxy-benzonitrile. This compound was then used to form the corresponding tetrazole via the method described in Example 3.

The title compound was prepared via the substitution method described in Example 21 by mesylate 2 from Example 3 and 5- (3-bromo-4-methoxy-benzonitrile) -1H-tetrazole from 57A and Then, hydrolysis of the ethyl ester was carried out by the procedure of Example 22.

[M + Na] + = 724.91.

Example 58. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112007053853814-pct00562
, Q is absent, Y = 4- (methylcyclopropane) phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

58A. Tetrazole formation

Tetrazole of this example was prepared by dissolving 4-cyano-phenyl in DMF solvent, adding (bromomethyl) cyclopropane, and stirring at room temperature for 3 to 12 hours. The resulting reaction mixture was diluted with EtOAc and washed with water and brine. The resulting organic phase was dried over Na 2 SO 4 and concentrated in vacuo to yield 4- (methylcyclopropane) benzonitrile. This compound was then used to form the corresponding tetrazole via the method described in Example 3.

The title compound was prepared via the substitution method described in Example 21 by 5- (4- (methylcyclopropane) -phenyl) -1H-tetrazole from 58 and A of mesylate 2 from Example 3, and then carried out. Hydrolysis of the ethyl ester was performed by the procedure of Example 22.

[M + Na] + = 686.29.

Example 59. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112007053853814-pct00563
, Q is absent, Y = 3-chloro (methylcyclopropane) phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by using ethyl ester title compound without workup from Example 21, adding (bromomethyl) cyclopropane and stirring at 60 ° C. for 3 to 12 hours. The mixture was cooled to rt and poured into a 50:50 EtOAc: water mixture, then washed with water and concentrated in vacuo. The resulting crude ethyl ester compound was hydrolyzed to a free acid by the procedure described in Example 22.

[M + Na] + = 720.24.

Example 60. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00564
, Q is absent, Y = 3-chloro-4-methoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by methyl iodide by the title compound of Example 21 and the procedure described in Example 59.

[M + Na] + = 680.23.

Example 61. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00565
, Q is absent, Y = 3-chloro-4-ethoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the title compound of Example 21 and ethyl iodide by the procedure described in Example 59.

[M + Na] + = 694.28.

Example 62. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00566
, Q is absent, Y = 3-bromo-4-ethoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by ethyl iodide precursor of the title compound of Example 23 and ethyl iodide by the procedure described in Example 59.

[M + Na] + = 740.17.

Example 63. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00567
, Q is absent, Y = 3-chloro-4- (2-hydroxyethoxy) phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared with 2-iodineethanol by the title compound of Example 21 and the procedure described in Example 59.

Example 64. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00568
, Q is absent, Y = 3-bromo-4- (2-hydroxyethoxy) phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared with 2-iodineethanol by the ethyl ester precursor of the title compound of Example 23 and the procedure described in Example 59.

[M + Na] + = 754.27.

Example 65. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00569
, Q is absent, Y = 3-chloro-4- (O-allyl) phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by 3-iodinepropene by the procedure described in Example 59 with the title compound in Example 23.

[M + Na] + = 706.24.

Example 66. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112005043726247-pct00570
, Q is absent, Y = 3-bromo-4- (O-allyl) phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by 3-iodine propene by the procedure described in Example 59 with the ethyl ester precursor of the title compound of Example 23.

[M + Na] + = 752.15.

Example 67. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W

Figure 112005043726247-pct00571
, Q is absent, Y = 3-chloro-4- (O-CH 2 SCH 3 ) phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by Cl-CH 2 SCH 3 by the title compound of Example 23 and the procedure described in Example 59.

Example 68. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112009026180213-pct01030
, Q = absent, Y = 3-bromo-4- (O-CH 2 SCH 3 ) phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The main compound is prepared as an ethyl ester precursor in CI-CH 2 SCH 3 according to the main compound of Example 23 and the procedure described in Example 59.

[M + Na] + = 752.15

Example 69. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112009026180213-pct00573
, Where Q '=-CH 2- , Y =
Figure 112009026180213-pct00574
, j = 3, m = s = 1, and R 3 = R 4 = H.

Figure 112005043726247-pct00575

69A. Preparation of Cyanoproline Derivatives (69b)

Cis-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (69a) (3.94 g, 16.06 mmol) in CH 2 Cl 2 (40 ml) at 0 ° C. To the solution of was added dropwise DIEA (4.3 ml) and methanesulfonyl chloride (1.40 ml). After addition, the mixture was stirred for 1.5 hours. The reaction was completed by measuring by TLC analysis (50% EtOAc-hexane was used to develop TLC). The mixture was diluted with EtOAc and sat. Washed with NaHCO 3 , brine and dried (Na 2 SO 4 ). After evaporation of the solvent, the oil residue was used in the next step without further purification. [M + H] + = 324.

The crude product from the previous step was dissolved in DMF (35 ml) and floured KCN (2.5 g) was added. The mixture was heated to 90 ° C. After cooling to rt, the mixture was diluted with EtOAc, washed with H 2 O and brine and dried over Na 2 SO 4 . The crude product was purified by silica gel chromatography (20% EtOAc / hexanes).

[M + H] + = 255.

69B. Preparation of Tetrazolyl Proline Derivatives (69c)

To toluene (8 ml) was added NaN 3 (684 mg, 10.53 mmol) and Et 3 N.HCl (1.45 g, 10.53 mmol) to a solution of nitrile 69b (669 mg, 2.63 mmol). The mixture was heated at 115 ° C. for 18 h. The mixture was diluted with CH 2 Cl 2 , washed with 5% aqueous citric acid solution and dried over Na 2 SO 4 . Evaporation of the solvent gave crude product 69cEt 3 N addition (660 mg).

[M + H] + = 298.

69C. Preparation of 5-biphenylmethyl-tetrazolyl proline (69d and 69e)

To a solution of 69c (92.8 mg, 0.31 mmol) in THF (2 ml) was added 4-phenylbenzyl bromide (90.4 mg, 0.37 mmol) and K 2 CO 3 (140 mg, 1.01 mmol). The mixture was heated at 65 ° C. overnight, diluted with EtOAc, washed with brine and dried over Na 2 SO 4 . After evaporation of the solvent, the crude product was dissolved in THF-MeOH-H 2 O (2 ml: 1 ml: 1 ml) and LiOH (130 mg) was added. The mixture was stirred at rt overnight. THF and MeOH were evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with 5% citric acid and dried over Na 2 S0 4 . Evaporation of the solvent gave crude products 69d and 69e.

[M + Boc + H] + = 350.

69D. Preparation of Tripeptide (69 g)

To a solution of 69d and 69e (about 0.31 mmol) of DMF (2.0 ml) was added sequentially D-β-vinyl cyclopropane amino acid ethyl esterHCl (66 mg), DIEA (0.25 ml) and HATU (164 mg). . The mixture was stirred for 1 h and then diluted with EtOAc, washed with brine, 5% citric acid and dried over Na 2 SO 4 . After evaporation of the solvent, the residue was dissolved in 2 ml of CH 2 Cl 2 and 2 ml of 4N HCl was added to dioxane. The mixture was stirred at rt for 1.5 h. The solvent was evaporated. The residue is dissolved in EtOAc and sat. Neutralized with NaHCO 3 , washed with brine and dried over Na 2 SO 4 . After evaporation of the solvent, the residue was dissolved in DMF (2 ml) and P3 (120 mg), DIEA and HATU were added sequentially. The resulting mixture was stirred and monitored by TLC analysis. After the reaction was completed, the mixture was diluted with EtOAc, brine, 5% citric acid, sat. NaHCO 3 , again washed with brine. The organic solution was dried over Na 2 S0 4 and evaporated under vacuum to give crude product mixture purified by silica gel chromatography (30% to 50% EtOAc-hexane).

[M + H] + = 740.

69E. Closed ring metathesis (69h and 69i).

Figure 112006092596674-pct01031

A mixture of 69f and 69g (60 mg) is dissolved in dry CH 2 Cl 2 to make about 0.01 molarity. This solution is carefully degassed with N 2 flow for 15 minutes. 5% mole of Hoveida's catalyst was added under N 2 . The mixture is refluxed overnight. The solvent is evaporated. The residue is loaded onto a silica gel column and eluted with 10% EtOAc to remove the catalyst. Two regioisomers are eluted and separated by 30-40% EtOAc-hexanes to give a smaller polar product 69j (37.9 mg) and a larger polar product (69k) (14.8 mg). Regioisomers of 69j and 69k were determined by NMR analysis.

[M + H] + = 712.

69F. Ethyl ester hydrolysis (69j)

Ester 69h (37.9 mg) was dissolved in THF-MeOH-H 2 O (2 ml: 1 ml: 1 ml) and LiOH (21 mg) was added. The mixture was stirred at rt overnight. THF and MeOH were evaporated under reduced pressure. The residue is dissolved in EtOAc, washed with 5% citric acid and dried over Na 2 SO 4 . Evaporation of the solvent gave the crude product. The crude product is purified by silica gel chromatography (5% MeOH in CH 2 Cl 2 ) to give the main compound 69j.

[M + H] + = 684.

Example 70. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112009026180213-pct00577
, Where Q '=-CH 2- , Y =
Figure 112009026180213-pct00578
, j = 3, m = s = 1, and R 3 = R 4 = H.

Ester 69i (14.8 mg) was dissolved in THF-MeOH-H 2 O (2 ml: 1 ml: 1 ml) and LiOH (21 mg) was added. The mixture was stirred at rt overnight. THF and MeOH were evaporated under reduced pressure. The residue is dissolved in EtOAc, washed with 5% citric acid and dried over Na 2 SO 4 . Evaporation of the solvent gave the crude product. The crude product is purified by silica gel chromatography (5% MeOH in CH 2 Cl 2 ) to give the main compound 69k.

[M + H] + = 684.

Example 71. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 = cyclopentyl, G = OH, L = absent, W =

Figure 112009026180213-pct01032
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

71a- amine deprotection.
0.041 mmol of the main component of Example 21 was dissolved in 4 ml of 4M of HCl in dioxane and stirred for 1 hour. Reaction residue 71a was concentrated in vacuo .

delete

71b-chloroformate reagent

Chloroformate Reagent 71b was prepared by dissolving 0.045 mmol of cyclopentanol in THF (3 ml) and 0.09 mmol of phosgene in toluene (20%). The resulting reaction mixture was stirred for 2 hours at room temperature and the solvent was removed from the vacuole membrane. DCM was added to the residue and subsequently concentrated to dryness twice on the vacu membrane to give chloroformate reagent 71b.

71c-carbamate formation

The main carbamate was prepared by dissolving residue 71a in 1 ml of THF, adding 0.045 mmol of TEA, and cooling the resulting reaction mixture to 0 ° C. To this 0 ° C. reaction mixture was added chloroformate reagent 71b to 3 ml of THF. The resulting reaction mixture is reacted for 2 hours at 0 ° C., extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO 4 , and concentrated to dryness in a vesicle membrane. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure described in Example 22.

Example 72. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 = cyclohexyl , G = OH, L = absent, W is

Figure 112009026180213-pct00580
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the method described in Example 71 with the title compound and cyclobutanol of Example 21, followed by ethyl ester hydrolysis by the procedure described in Example 22.

Example 73. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 = cyclobutyl, G = OH, L = absent, W is

Figure 112009026180213-pct00581
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the method described in Example 71 with the title compound of Example 21 and cyclohexanol, followed by ethyl ester hydrolysis by the procedure described in Example 22.

Example 74. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 =

Figure 112009026180213-pct00582
, G = OH, L = absent, W is
Figure 112009026180213-pct00583
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the method described in Example 71 with the title compound of Example 21 and (R) -3-hydroxytetrahydrofuran, followed by ethyl ester hydrolysis by the procedure described in Example 22. .

Example 75. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 =

Figure 112009026180213-pct00584
, G = OH, L = absent, W is
Figure 112009026180213-pct00585
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by the method described in Example 71 with the title compound of Example 21 and (S) -3-hydroxytetrahydrofuran, followed by ethyl ester hydrolysis by the procedure described in Example 22. .

Example 76. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 =

Figure 112009026180213-pct00586
, G = OH, L = absent, W is
Figure 112009026180213-pct00587
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound is combined with the title compound of Example 21.

Figure 112007053853814-pct01041
Was prepared by the method described in Example 71, followed by ethyl ester hydrolysis by the procedure described in Example 22.

Example 77. A compound of Formula II wherein A =-(C = O) -R 1 , wherein R 1 = cyclopentyl, G = OH, L = absent, W is

Figure 112009026180213-pct00589
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by dissolving 0.041 mmol of the title compound of Example 21 in 4 ml of 4M of HCl in dioxane and stirring the reaction mixture for 1 hour. The reaction residue is concentrated in the vacuole membrane. To this residue, 4 ml of THF and 0.045 mmol of TEA were added, the mixture was cooled to 0 ° C., and 0.045 mmol of cyclopental acid chloride was added. The resulting reaction mixture was stirred at 0 ° C. for 2 hours. The reaction mixture is extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO 4 and concentrated to dryness on the vesicle membrane. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure described in Example 22.

Example 78. A compound of Formula II wherein A =-(C = O) -NH-R 1 , wherein R 1 = cyclopentyl, G = OH, L = absent, W is

Figure 112009026180213-pct00590
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by dissolving 0.041 mmol of the title compound from Example 21 in 4 ml of 4M of HCl in dioxane and stirring the reaction mixture for 1 hour. The resulting reaction residue was concentrated on the vacuole membrane, dissolved in 4 ml of THF and cooled at 0 ° C. 0.045 mmol of cyclopentyl isocyanate was added to the 0 ° C. solution and the resulting reaction mixture was stirred at RT for 4 h. The solution is extracted with EtOAc, washed with 1% HCl, water and brine, dried over MgSO 4 and concentrated to dryness on the vesicle membrane. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure described in Example 22.

Example 79. A compound of Formula II wherein A =-(C = S) -NH-R 1 , wherein R 1 = cyclopentyl, G = OH, L = absent, W is

Figure 112009026180213-pct00591
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by dissolving 0.041 mmol of the title compound from Example 21 in 4 ml of 4M of HCl in dioxane and stirring for 1 hour. The resulting reaction residue was concentrated on the vacuole membrane, dissolved in 4 ml of THF and cooled at 0 ° C. 0.045 mmol of cyclopentyl sulphonylchloride TEA 0.045 mmol was added to the 0 ° C. solution and the resulting reaction mixture was stirred at RT for 4 h. The solution is extracted with EtOAc, washed with 1% HCl, water and brine, dried over MgSO 4 and concentrated to dryness on the vesicle membrane. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure described in Example 22.

Example 80. A compound of Formula II wherein A = -S (O) 2 -R 1 , R 1 = cyclopentyl, G = OH, L = absent, W is

Figure 112009026180213-pct00592
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared by dissolving 0.041 mmol of the title compound from Example 21 in 4 ml of 4M of HCl in dioxane and stirring the reaction mixture for 1 hour. The resulting reaction residue was concentrated in a vacuole membrane, dissolved in 4 ml THF and cooled at 0 ° C. 0.045 mmol of cyclopentyl sulphonyl chloride TEA 0.045 mmol was added to the 0 ° C. solution and the resulting reaction mixture was stirred at RT for 4 h. The solution is extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO 4 and dried over vacuole membrane. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure described in Example 22.

Example 81. A compound of Formula II wherein A =-(C = O) -OR 1 , R 1 = cyclopentyl, G = -O-phenethyl, L = absent, W is

Figure 112009026180213-pct00593
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

Figure 112005043726247-pct00594

The title compound was prepared by addition of the solution of the title compound of Example 71 and the phenethyl alcohol 81a in 0.5 ml DCM had 1.2 eq. PyBrOP, 4eq. The catalyst amount of DMAP in DIEA and 0 degreeC is added. The resulting reaction mixture was stirred at 0 ° C. for 1 hour and heated to RT in a cycle of 4-12 hours. The reaction mixture was subjected to silica gel flash chromatography using a different ratio of hexanes: EtOAc as the eluting phase (9: 1-> 5: 1-> 3: 1-> 1: 1) to obtain the title compound isolated phenethyl ester 81b. It is purified by chromatography.

Other esters can be made using the same procedure.

Example 82. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 = cyclopentyl, G = -NH-phenethyl, L = absent, W is

Figure 112009026180213-pct00595
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

Figure 112005043726247-pct00596

The title compound is added at 0 ° C. in 0.5 ml DMF, EDC (1.2 eq.) And DIEA (4 eq.) With a solution of the main chemical of Example 71. The resulting reaction mixture was stirred for 1 hour. In turn, the reaction was preheated to RT in a cycle of 4-12 hours. The reaction mixture was subjected to silica gel flash chromatography using different ratios of hexanes: EtOAc as the elution phase (9: 1-> 5: 1-> 3: 1-> 1: 1) to allow the main compound phenethyl amide 82b. Purified by Other esters can be made using the same procedure.

Example 83. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 = cyclopentyl, G = -NHS (O) 2 -phenethyl, L = absent, W is

Figure 112009026180213-pct00597
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

Figure 112005043726247-pct00598

The title compound was added with a solution of the title compound of Example 71 and had an α-toluenesulfonamide 83a (10 mg) in 0.5 ml DCM having 1.2 eq. PyBrOP, 4eq. The catalytic amount of DIEA, and DMAP was added at 0 ° C. The resulting reaction mixture was stirred for 1 hour and preheated over a period of 4-12 hours. The reaction mixture was subjected to silica gel flash chromatography using different ratios of hexanes: EtOAc as the eluting phase (9: 1-> 5: 1-> 3: 1-> 1: 1) to give the main compound phenethyl ester 83b. Purified by

Other esters can be made using the same procedure.

Example 84. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 = cyclopentyl, G =-(C = O) -OH, L = absent, W is

Figure 112009026180213-pct00599
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

Figure 112006092596674-pct01033

The title compound was added a solution of the main chemical of Example 71 in 0.5 ml THF and α-hydroxy-α-methyl-propionitrile (0.1 ml) and catalytic amount TFA were added at 0 ° C. The resulting reaction mixture was preheated from 0 ° C. to RT over a 4-12 hour cycle hydrolyzed with dioxane to concentrated hydrochloric acid. The reaction was extracted with EtOAc and washed with water and brine to give the crude form α-hydroxy compound 84a. Crude compound 84a undergoes Dess-Martin oxidation in THF (0.5 ml) and provides a crude form of a-carbonyl compound. Crude compound 84b was prepared using a different ratio of hexanes: EtOAc as eluent phase (9: 1-> 5: 1-> 3: 1-> 1: 1) to allow the title compound isoleated keto acid 84b. Purification by flash chromatography.

Example 85. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 = cyclopentyl, G =-(C═O) -O-pentethyl, L = absent, W is

Figure 112009026180213-pct00601
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared from the title compound keto acid of Example 84 and penethanol according to the procedure described in Example 81.

Example 86. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 = cyclopentyl, G =-(C = O) -NH-phenethyl, L = absent, W is

Figure 112009026180213-pct00602
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared with the main compound keto acid of Example 84 and phenethyl amine according to the procedure described in Example 82.

Example 87. A compound of formula II wherein A =-(C = O) -OR 1 , wherein R 1 = cyclopentyl, G =-(C = O) -NH-S (O) 2 -benzyl, L = Absence, W is

Figure 112009026180213-pct00603
, Q = absent, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H.

The title compound was prepared with the main compound keto acid of Example 84 and α-toluenesulfonamide according to the procedure described in Example 83.

Example 88. A compound of Formula II wherein A = tBOC, G = OH, L =-(C = O) CH 2- , W is

Figure 112009026180213-pct00604
, Q = absent, Y = phenyl, j = 1, m = s = 1, and R 3 = R 4 = H.

Figure 112005043726247-pct00605

(2S) -N- Boc -Amino-5-oxo-non-8- Enoic  synthesis

88A. The aforementioned amino acids were prepared by adding a solution of the monoallyl ester of malonic acid of dry THF under N 2 in -78 ° C., n-Bu 2 MG droplets at a cycle of 5 minutes. The resulting suspension was stirred for 1 h at RT and evaporated to dryness. Solid Mg salt 88b was dried under vacuum.

The glutamic acid derivative 88a is first mixed with 1.1'-carbonyldiimidazole in anhydrous THF, the mixture is stirred at RT for 1 hour, and the free acid moiety is activated. In turn, the activated glutamic acid derivative was placed in a solution of Mg 88b and the resulting reaction mixture was stirred at RT for 16 h. The mixture was diluted with ethyl acetate and the organic solution was washed with 0.5 N HCl (at 0 ° C.) and brine, dried and evaporated. The residue obtained was dissolved via silica chromatography with 35-40% ethyl acetate in a hexane elution system to yield diester 88c.

88B. To the stirred solution of tetrakis (triphenylphosphine) PD (0) in dry DMF was added diester in DMF. The mixture was stirred at RT for 3.5 h. DMF was evaporated under reduced pressure and the residue was diluted with EtOAc. EtOAc solution was washed with 0.5N 0 ° C. HCl, brine, dried and evaporated. The residue was chromatographed on silica gel using 15-20% EtOAc in hexane as eluent to yield the methyl ester intermediate.

The methyl ester intermediate is diluted with THF and water, then LiOH.H 2 O is added and the resulting mixture is stirred at RT for 25 hours and the completion of hydrolysis is monitored by TLC. The reaction mixture is concentrated under vacuum to remove the majority of THF and further diluted with methylene chloride. The resulting solution was washed with 1 N HCl, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. To remove fine impurities and excess Boc 2 O, the crude product is purified via flash chromatography using a 100% hexanes-> 100% EtOAc solvent gradient as eluent. (2S) -N-Boc-amino-5-oxo-non-8-enoic acid 88d is obtained. Further explanation of previous amino acid synthesis can be found in T. Tsuda et al. J. Am. Chem. Soc., 1980, 102, 6381-6384 and WO 00/59929, the contents of which are incorporated herein by reference in their entirety.

88C. Between the modified click peptide precursor mesylate

The modified cyclic peptide precursor mesylate is (2S) -N instead of Boc-L-2-amino-8-nonenoic acid (1a) followed by conversion to the corresponding mesylate via the method described in Example 2. Prepared using the synthetic route detailed in Example 1 using -Boc-amino-5-oxo-8-enoic acid 88d.

The title compound was reacted with 5-phenyl-1H-tetrazol by the modified cyclic peptide precursor mesylate formed at 88C and the substitution method eluted in Example 21 following hydrolysis of ethyl ester via the method described in Example 22. Ready.

Example 89. A compound of Formula II wherein A = tBOC, G = OH, L = -CH (CH 3 ) CH 2- , W is

Figure 112009026180213-pct00606
, Q = absent, Y = phenyl, j = 1, m = s = 1, R 3 = methyl, and R 4 = H.

Figure 112005043726247-pct00607

(2S, 5R) -N- Boc -2-amino-5- methyl -Non-8- Enoic acid  Synthesis of (89h)

89A. Solid ethyl 2-acetamidomaronate 89b was added (R)-(+)-citronellal 89a to a solution of pyridine over 1 minute. The resulting solution was cooled in a 10 ° C. bath and acetic anhydride added over 4 minutes. The resulting solution was stirred for 3 h at RT and another portion of ethyl 2-acetamidomarate 89b was added. The resulting mixture was stirred for an additional 11 h at RT. Ice is added and the solution is stirred for 1.5 hours, the mixture is diluted with 250 ml water and extracted into two portions of wther. The organic phase is 1N HCl, sat. NaHCO 3 , dried Na 2 SO 4 , washed and purified by flash chromatography (40% EtOAc / hexanes) to yield compound 89c.

89B. To the degassed solution of 89c in dry ethanol, (S, S) -Et-PUPHOS Rh (COD) OTf was added. The mixture was stirred in a Parr shaker for 2 hours at 30 psi of hydrogen. The resulting mixture was evaporated to dryness to afford crude compound 89d which was used in the next step without purification.

89C. Compound 89d was dissolved in a mixture of tBuOH / acetone / H 2 O (1: 1: 1) and placed in an ice bath (0 ° C.). NMMO and O S O 4 were added sequentially and the reaction mixture was stirred at RT for 4 h. Most of the acetone is removed by evaporation under vacuum and the mixture is extracted with ethyl acetate. The organic layer was further washed with water and brine, dried over anhydrous MgSO 4 and evaporated to dryness. Diol 89e was obtained in high purity after flash column chromatography using 1% ethanol in ethyl acetate as eluent.

89D. NalO 4 was added to a solution of THF / H 2 O (1: 1) diol 89e at 0 ° C. and the reaction mixture was stirred at RT for 3.5 h. Most of the THF solvent is removed sequentially by evaporation under vacuum and the remaining mixture is extracted with EtOAc. The combined organic layer was further washed with 5% aqueous citric acid solution, 5% aqueous NaHCO 3 and brine, and then the organic phase was dried over MgSO 4 and evaporated to dryness in vacuo. Aldehyde intermediate 89f is used in the next step in crude form.

89E. To a solution of Ph 3 PCH 3 Br in anhydrous toluene, KHMDS is added, which forms a stirred suspension at RT for 30 minutes under N 2 . After stirring, the suspension was cooled to 0 ° C., a solution of aldehyde intermediate 89f of THF was added, and the mixture was preheated to RT and stirred for 1 hour. Most of the THF was evaporated under vacuum, EtOAc was added to the mixture and the organic phase was washed with water, 5% aqueous NaHCO 3 and brine. 89 g of pure compound was purified by flash chromatography on silica gel using hexane; EtOAc (3: 2) as eluent and then separated.

89F. To a solution of 89 g of THF stock solution, Boc 2 O, and DMAP are added and the reaction mixture is heated to reflux for 2.5 hours. Subsequently, the majority of THF is evaporated and the crude mixture is diluted with methylene chloride and washed with 1N HCl to remove DMAP. The organic layer is further extracted with saturated aqueous NaHCO 3 , dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The crude product is diluted with THF and water, LiOH.H 2 O is added and the resulting mixture is stirred at RT for 25 hours and the completion of hydrolysis is monitored by TLC. The reaction mixture is concentrated under vacuum to remove the majority of THF and further diluted with methylene chloride. The resulting solution is washed with 1 N HCl, dried over anhydrous Na 2 SO 4 and concentrated under vacuum. To remove fine impurities and excess Boc 2 O, the crude product is purified via flash chromatography using a 100% hexanes-> 100% EtOAc solvent gradient as eluent. (2S, 5R) -N-Boc-2-amino-5-methyl-non-8-enoic acid 89h is obtained. Further description of previous amino acid synthesis is disclosed in WO 00/59929, the contents of which are incorporated herein by reference in their entirety.

89G. Deformed Cyclic  Peptide precursor Mesylate  synthesis

The modified cyclic peptide precursor mesylate is substituted for Boc-L-2-amino-8-nonenoic acid (1a) following the conversion to the corresponding mesylate via the method described in Example 2 ((2S, 5R) -N-Boc-2-amino-5-methyl-non-8-enoic acid (89h) was prepared using the synthetic route described in Example 1 above.

The title compound was prepared with 89G modified cyclic peptide precursor mesylate and 5-phenyl-1H-tetrazole by an alternative method eluted in Example 21 following hydrolysis of ethyl ester via the method described in Example 22. .

Example 90. A compound of formula II wherein A = tBOC, G = OH, L = -O-, W

Figure 112009026180213-pct00608
, Q = absent, Y = phenyl, j = 0, m = s = 1, R 3 = methyl, and R 4 = hydrogen.

Figure 112005043726247-pct00609

Synthesis of N-Boc-O-allyl- (L) -threonine (90d)

90A. Boc- (L) -threonine 90a is partially dissolved in methylene chloride / methanol at 0 ° C. A solution of diazomethane in diethyl ether is added to yellow indicating the presence of diazomethane. When the solvent evaporates, crude methyl ester 90b is obtained.

90B. Intermediate 90b is dissolved in anhydrous diethyl ether and Ag 2 O is added to activate freshly with a 4 ′ molecular sieve. Finally, allyl iodide is added to the reaction mixture and stirred at reflux. After a period of 20 hours and 30 hours an additional portion of allyl iodide is added to the reaction mixture twice and the stirring is continued for a total of 36 hours. The mixture is then filtered through celite and purified by flash chromatography on silica gel using EtOAc / hexane (1: 4) as eluent to give compound 90c.

90C. Compound 90c is dissolved in a mixture of THF / MeOH / H 2 O (2: 1: 1) and LiOH.H 2 O is added. The solution is stirred for 2 h at room temperature, acidified to pH ˜3 with 1N HCl and then the solvent is removed under vacuum. Obtained crude compound 90d is obtained. For a more detailed description of the foregoing amino acid synthesis, see WO 00/59929, which is incorporated herein by reference in its entirety.

90D. Synthesis of when the modified click (cyclic) peptide precursor mesylate (mesylate)

The modified cyclic peptide precursor mesylate is synthesized as described in Example 1 using N-Boc-O-allyl- (L) -threonine 90d instead of Boc-L-2-amino-8-nonenoic acid 1a. Prepared by using the route and then converting to the corresponding mesylate via the method described in Example 2.

The title compound is the 5-phenyl-1H-tetrazole and the modified cyclic peptide precursor mesylate formed at 90D by the alternative method described in Example 21, hydrolysis of the ethyl ester via the method disclosed in Example 22. It is prepared by following.

Example 91. A compound of Formula II wherein A = tBOC , G = OH, L = -S-,

W is

Figure 112009026180213-pct00610
, Q = absent, Y = phenyl, j = 0, m = s = 1, R 3 = methyl, R 4 = hydrogen.

Figure 112005043726247-pct00611

(2S, 3S) -N- Boc -2-amino-butanoic acid 3 Synthesis of (methoxy mercaptomethyl-allyl) (91e)

91A. Compound 91a is dissolved in pyridine, the solution is cooled to 0 ° C. in an ice bath and a small amount of tosyl chloride is added to separate the reaction mixture between diethyl ether and H 2 O. The ether layer is also washed with 0.2 N HCl and brine, dried over anhydrous MgSO 4 , filtered and concentrated to dryness in vacuo. Purification of the crude material by flash chromatography on silica gel using hexanes / EtOAc (gradient 8: 2 to 7: 3 ratio) as eluent resulted in the separation of tosyl derivative 91b.

91B. For a solution of tosyl derivative 91b in anhydrous DMF, potassium thioacetate is added and the reaction mixture is stirred at room temperature for 24 hours. And most of the DMF is evaporated under vacuum and the remaining mixture is separated between EtOAc and H 2 O. The aqueous layer is reextracted with EtOAc and the combined organic layers are washed with brine, dried over anhydrous MgSO 4 and evaporated to dryness. Purification of the crude material by flash chromatography on silica gel using hexane / EtOAc (4: 1 ratio) as the eluent provides thioester 91c.

91C. H 2 O / EtOH (3: 5 ratio) and a 0.2 M NaOH aqueous solution are added to an aqueous solution of thioester 91c, and the mixture is stirred at room temperature for 1.5 hours. And allyl iodide is added and stirring is continued for 30 minutes at room temperature. The reaction mixture is concentrated to half of the original volume and then extracted with EtOAc. The aqueous layer is acidified to pH ˜3 with cold aqueous 0.5N HCL and reextracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous MgSO 4 , evaporated to dryness in vacuo. The crude reaction mixture comprises at least four products; All products are separated after flash chromatography on silica gel using hexanes / EtOAc (gradients 9: 1 to 3: 1). Desired product 91d is a least polar compound.

91D. A solution 91d in MeOH / H 2 O (3: 1) is mixed with aqueous NaOH (0.3 N) for 24 hours at room temperature and 1 hour at 40 ° C. The reaction mixture is acidified with cold aqueous 0.5 N HCl, MeOH is removed under vacuum and the remaining aqueous mixture is extracted with EtOAc. The organic phase is dried over MgSO 4 and evaporated to dryness to yield compound 91e. For a more detailed description of the foregoing amino acid synthesis, see WO 00/59929, the entire contents of which are incorporated herein by reference.

91E. When the modified click peptide synthesis of the precursor mesylate

Modified cyclic peptide precursor mesylate replaces Boc-L-2-amino-8-nonenoic acid 1a (2S, 3S) -N-Boc-2 amino-3 (mercaptoallyl) butanoic acid (91e) Prepared using the synthetic route described in Example 1, followed by conversion to the corresponding mesylate via the process described in Example 2.

Hydrolysis of the ethyl ester via the process disclosed in Example 22, with the modified cyclic peptide precursor mesylate formed from 91E and 5-phenyl-1H-tetrazole by the alternative method described in Example 21. It is prepared by following.

Example 92. A compound of Formula II wherein A = tBOC , G = OH, L = -S (O) —,

W is

Figure 112009026180213-pct00612
, Q = absent, Y = phenyl, j = 2, m = s = 1, R 3 = methyl, R 4 = hydrogen.

Modified amino acids

Figure 112007053853814-pct00613
Formation of

92A. Modified amino acids are prepared by dissolving sodium metaperiodate (1.1 eq.) In water and cooling to 0 ° C. in an ice bath followed by dropwise addition of an aqueous solution of Compound 91d in dioxane. do. The resulting reaction mixture is stirred at 0 ° C. for 1 hour at 40 ° C. for 4 hours. The reaction mixture is concentrated and water is added and the mixture is extracted twice with methylene chloride. The combined organic layers are washed with water, brine, dried over anhydrous MgSO 4 and concentrated in vacuo. And methyl ester is reduced via the method described in Example 91D to reach modified amino acid 92a. Further details of the foregoing amino acid synthesis are described in T. Tsuda et al, J. Am. Chem. Soc ., 1980, 102 , 6381-6384 and WO 00/59929.

92B. When the modified click peptide synthesis of the precursor mesylate

The modified cyclic peptide precursor mesylate was described in Example 2 using the synthetic route described in Example 1 using modified amino acid 92a instead of Boc-L-2-amino-8-nonenoic acid 1a. Prepared by conversion to the corresponding mesylate via the process.

The title compound was hydrolyzed ethyl ester via the method disclosed in Example 22, with modified cyclic peptide precursor mesylate formed in 5-phenyl-1H-tetrazole and 92B by the alternative method described in Example 21. It is prepared by following.

Example 93. A compound of Formula II wherein A = tBOC , G = OH, L = -S (O) 2- ,

W is

Figure 112009026180213-pct00614
, Q = absent, Y = phenyl, j = 2, m = s = 1, R 3 = methyl, R 4 = H

Modified amino acids

Figure 112005043726247-pct00615
Formation of

93A. Modified amino acids are prepared by dissolving sodium metaperiodate (1.1 eq.) In water, cooling to 0 ° C. in an ice bath, and then dropwise adding the compound 92d solution in dioxane. The resulting reaction mixture is stirred at 0 ° C. for one hour at 40 ° C. for 4 hours. The reaction mixture is concentrated and water is added and the mixture is extracted twice with methylene chloride. The combined organic layer is washed with water, brine, dried over anhydrous MgSO 4 and concentrated in vacuo. The methyl ester is then reduced via the method described in Example 91D to reach modified amino acid 93a. Further details of the foregoing amino acid synthesis are described in T. Tsuda et al., J. Am. Chem. Soc ., 1980, 102 , 6381-6384 and WO 00/59929.

93B. When the modified click peptide synthesis of the precursor mesylate

The modified cyclic peptide precursor mesylate was prepared using the synthetic route described in Example 1 using Boc-L-2-amino-8-nonenoic acid (1a) followed by the corresponding method through the method described in Example 2. It is prepared by the conversion to mesylate.

The title compound is a modified cyclic peptide precursor mesylate formed in 5-phenyl-1H-tetrazole and 93B by the alternative method described in Example 21, followed by the ethyl ester via the method described in Example 22. It is prepared by hydrolysis.

Example 94. A compound of Formula II wherein A = tBOC , G = OH, L = -SCH 2 CH 2- .

W is

Figure 112009026180213-pct00616
, Q = absent, Y = phenyl, j = 0, m = s = 1, and R 3 = R 4 = CH 3

Figure 112005043726247-pct00617

94A. Synthesis of (S) -N- Boc -2-amino-3- methyl- 3 (1 -mercapto -4 -butenyl ) butanoic acid (94b)

L-Phenylamine 94a is dissolved in DMF / DMSO (5: 1), and then 4-bromopentene and CsOH.H 2 O are added to this mixture and stirring is continued for a further 12 hours. The DMF is then removed under vacuum and the remaining mixture is diluted with 0.5N HCL at 0 ° C. to adjust the pH to ˜4-5 and then extract two portions of EtOAc. The organic phase is washed with brine (2x), dried over MgSO 4 and evaporated to give crude carboxylic acid 94a. For further details regarding the foregoing amino acid synthesis, see WO 00/59929, which is incorporated herein by reference in its entirety.

94B. When the modified click peptide synthesis of the precursor mesylate

Modified cyclic peptide precursor mesylate was prepared in the following example using the synthetic route described in Example 1 using modified amino acid 94a instead of Boc-L-2-amino-8-nonenoic acid 1a. By conversion to the corresponding mesylate via the process described in 2.

The title compound is a modified cyclic peptide precursor mesylate formed in 5-phenyl-1H-tetrazole and 94B by the alternative method described in Example 21, followed by the ethyl ester via the method described in Example 22. It is prepared by hydrolysis.

Example 95. A compound of Formula II wherein A = tBOC , G = OH, L = —CF 2 CH 2 —.

W is

Figure 112009026180213-pct00618
, Q = absent, Y = phenyl, j = 1, m = s = 1, and R 3 = R 4 = H

Figure 112005043726247-pct00619

(2S) -N- Boc -Amino-5- Difluoro -Non-8- Of enoic acid (95b)  synthesis

95A. To a solution of the ketone compound 88d (0.30 g, 1 mmol) in 5 ml DCM is added DAST (Diethylaminosulfurtrifluoride, 0.2 g, 1.2 eq). The reaction is maintained at room temperature for 2-3 days. The solvent was evaporated and the residue was purified by silica gel flash chromatography using different ratios of hexanes: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) as eluent to separate methyl ester. Get 95a. For further details regarding this synthesis see Tius, Marcus A et al., Tetrahedron , 1993 , 49 , 16; 3291-3304.

95B. Methyl ester 95a is dissolved in THF / MeOH / H 2 O (2: 1: 1) and LiOH.H 2 O is added. The solution was stirred at room temperature for 2 hours, then acidified with 1N HCl to pH ˜3, and then the solvent was removed in vacuo to give crude (2S) -N-Boc-amino-5-difluoro- Obtain non--8-enoic acid 95b.

95C. When the modified click peptide synthesis of the precursor mesylate

Modified cyclic peptide precursor mesylate is crude (2S) -N-Boc-amino-5-difluoro-non- instead of Boc-L-2-amino-8-nonenoic acid (1a). Prepared by conversion to the corresponding mesylate via the method described in Example 2 below, using the synthetic route described in Example 1 using 8-enoic acid 95b.

The title compound is a modified cyclic peptide precursor mesylate formed at 5-phenyl-1H-tetrazole and 95C by the alternative method described in Example 21, followed by the hydrolysis of the ethyl ester via the method described in Example 22. Prepared by decomposition.

Example 96. A compound of Formula II wherein A = tBOC , G = OH, L = -CFHCH 2- .

W is

Figure 112009026180213-pct00620
, Q = absent, Y = phenyl, j = 1, m = s = 1, and R 3 = R 4 = H

Figure 112005043726247-pct00621

(2S) -N- Boc -Amino-5- Fluoro -Non-8- Of enoic acid (96c)  synthesis

96A. To a solution of ketone compound 88d in 5 ml methanol, NaBH 4 (2.2 eq) is added. The reaction mixture is stirred at room temperature for 2-6 hours, after which the reaction is terminated with 1M ammonium chloride and extracted with EtOAc (30 ml). The solvent is evaporated to give crude hydroxy compound 96a.

96B. The hydroxy compound 96a is dissolved in 5 ml DCM, to which DAST (0.2 g, 1.2 eq) is added and stirred at -45 ° C for 1 hour. The reaction mixture is then warmed to room temperature and stirred for 2-3 days. The solvent was evaporated and the residue was purified by silica gel flash chromatography using different ratios of hexanes: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) as eluent to separate monofluoro To give the compound methyl ester 96b. Further details regarding this synthesis can be found in Buist, Peter H et al., Tetrahedron Lett. , 1987 , 28 , 3891-3894.

96C. Methyl ester 96b is dissolved in THF / MeOH / H 2 O (2: 1: 1) and LiOH.H 2 O is added. The solution was stirred at room temperature for 2 hours, then acidified with 1N HCl to pH ˜3, and then the solvent was removed in vacuo to give crude (2S) -N-Boc-amino-5-difluoro- Non-8-enoic acid 96c may be provided.

96D. Synthesis of Modified Cyclic Peptide Precursor Mesylate

Modified cyclic peptide precursor mesylate is crude (2S) -N-Boc-amino-5-monofluoro-non- instead of Boc-L-2-amino-8-nonenoic acid (1a). Prepared by conversion to the corresponding mesylate via the method described in Example 2 using the synthetic route described in Example 1 using 8-enoic acid 96b.

The compound of this title has a modified cyclic peptide precursor mesylate and 5-phenyl-1H-tetrazole formed at 96C, followed by an alternative method described in Example 21, followed by It is prepared by hydrolysis.

Example 97. A compound of Formula III wherein A = tBOC , G = OH, L = absence.

W is

Figure 112009026180213-pct00622
, Q = absent, Y = phenyl, j = 3, m = s = 1, R 3 = R 4 = H

97A. Saturated cyclic peptide precursor mesylate is prepared by catalytic reduction of mesylate cyclic peptide precursor 2 with Pd / C in MeOH in the presence of H 2 .

The compound of this title had saturated cyclic peptide precursor mesylate and 5-phenyl-1H-tetrazole formed at 97A, followed by an alternative method described in Example 21, followed by the process of ethyl ester via the method described in Example 22. It is prepared by hydrolysis.

Compounds of the invention exhibit potent inhibitory properties on HCV NS3 proteinases. The examples below describe the assays in which compounds of the invention were tested for anti-HCV effects.

Example 98. Triazole Synthesis

Representative triazole derivatives for use in preparing the compounds of the present invention can be prepared as described in the Examples below.

Figure 112005043726247-pct00623

The triazoles of the present invention can be prepared by reacting 4 mmol of alkyne compound 98a and 8 mmol of trimethylsilyl azide, which are commercially available or prepared from the process described below, in a 2 ml of xylene in a pressure tube at 140 ° C. for 24-72 hours. Can be. The resulting reaction mixture was directly separated by silica column to give triazole 98b in 30-90% yield.

Example 99 Alkyne Synthesis

99A. Sonogashira reaction

Figure 112005043726247-pct00624

Alkynes used in the present invention are degassed solutions of 4 mmol of primary alkyne compounds 99a, 4 mmol of aryl halides (Y-halide), and 1 ml of triethylamine, 10 ml of acetonitrile and PdCl 2 (PPh 3 2 ) 140 mg (0.2 mmol) and 19 mg (0.1 mmol) of CuI can be prepared by the Sonogashira reaction. The resulting reaction mixture is degassed and stirred at room temperature for 5 minutes. The reaction is then heated to 90 ° C. and stirred for 12 hours. The reaction mixture can then be concentrated in vacuo and purified by silica column to obtain substituted alkyne 98a in a yield of 60-90%.

99B. Alkynyl  Synthesis of Amide

Figure 112009026180213-pct00625

Additional alkynes used in the present invention can be prepared by reacting 22 mmol of DIEA, 11 mmol of BOP, and 10 mmol of alkynyl acid 99c with 11 mmol of amine 99b in 15 ml of DMF and stirring at room temperature for 3 hours. The reaction mixture was then extracted with ethyl acetate (2 × 50 ml), 1M NaHCO 3 (2 × 30 ml), water (2 × 30 ml), 5% citric acid (2 × 50 ml) and brine (2 × 30 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to give alkyne 99d in 90% yield.

Example 100. A compound of Formula II wherein A = tBOC , G = OH, L = absence.

W is

Figure 112009026180213-pct00626
, X = H, Y = 4-t-butylphenyl, j = 3, m = s = 1, R 3 = R 4 = H

Figure 112005043726247-pct00627

The title compound was prepared by the following method: 2 mmol (0.54 g) of Boc methyl ester azidoproline and 2.5 mmol of 4-tert-butylphenylacetylene 100b were dissolved in 2 ml of xylene and stirred at 110 ° C. for 12 hours. It was. The resulting reaction mixture was separated by direct silica column to separate isomers 100c and 100d in 90% yield.

The title compound was then formed by performing the RCM process described in Example 1 using 100b instead of hydroxyl proline, followed by hydrolysis of ethyl ester via the process described in Example 106.

[M + Na] + = 671.72

Example 101. A compound of Formula II wherein A = tBOC , G = OH, L = absence.

W is

Figure 112009026180213-pct00628
, X = 4-t-butylphenyl, Y = H, j = 3, m = s = 1, R 3 = R 4 = H

The title compound was prepared by performing the RCM process described in Example 1 using 100c instead of hydroxy proline, followed by hydrolysis of ethyl ester via the process described in Example 106.

[M + H] + = 649.44.

Example 102. A compound of Formula II wherein A = tBOC , G = OH, L = absence.

W is

Figure 112009026180213-pct00629
, X and Y together = phenyl, j = 3, m = s = 1, R 3 = R 4 = H

Figure 112005043726247-pct00630

Triazole-substituted proline corresponding to the title compound was dissolved 1.5 mmol (0.5 g) of hydroxyproline mesylate 102a and benzotriazole 102b in 5 ml of DMF, 9 mmol (2.9 g) of cesium carbonate were added, The resulting reaction mixture was prepared by stirring at 70 ° C. for 12 hours. The reaction mixture was extracted with EtOAc and washed with 1M sodium bicarbonate and brine. The organic layer was dried over MgSO 4 and concentrated in vacuo. The expected isomers 102c and 102d were separated via silica column chromatography.

The title compound is then formed through the RCM procedure described in Example 1 using 102d instead of hydroxyl proline, followed by the process described in Example 106. Hydrolysis is carried out.

[M + Na] + = 588.46

Example 103. A compound of Formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00631

X and Y are phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

The compound is formed through the RCM procedure described in Example 1 using 102c instead of hydroxyl proline, followed by hydrolysis of the ethyl ester through the procedure described in Example 106.

[M + Na] + = 588.50

Example 104. A compound of Formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00632

X = Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

Dissolve 1.5 mmol (0.5 g) of hydroxyproline mesylate 102a and 4.5 mmol of benzotriazole 102b in triazole-substituted proline corresponding to this compound, 5 ml of DMF. The reaction mixture was prepared by adding 9 mmol (2.9 g) cesium carbonate and stirring the resulting reaction mixture at 70 ° C. for 12 hours. The reaction mixture is extracted with EtOAc and washed with 1M sodium bicarbonate and brine. The organic layer is dried over MgSO 4 and concentrated in vacuo.

The compound is then formed via the RCM procedure described in Example 1 using the triazole substituted florin of this example instead of hydroxyl proline, followed by hydrolysis of the ethyl ester via the procedure described in Example 106.

[M + Na] + = 690.42

Example 105. Formula II compounds wherein A = tBOC, G = OEt, L = absent,

W =

Figure 112005043726247-pct00633
X = Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

Figure 112005043726247-pct00634

In the present compound, 0.041 mmol of the compound of Example 2 and 0.123 mmol of 4,5-diphenyltriazole were dissolved in 3 ml of DMF, and 0.246 mmol of cesium carbonate (80 mg) was added thereto. It prepares by making it react at 70 degreeC for 12 hours. The reaction mixture is then extracted with EtOAc and washed with 1M sodium bicarbonate (2x30ml) and water (2x30ml). The resulting organic solvent is concentrated and dried in vacuo.

Example 106 Formula II compounds wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00635
X = Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

The present compound is prepared by dissolving 0.041 mmol of the present compound of Example 105 in 3 ml of dioxane, adding 2 ml of 1M LiOH, and reacting at RT for 8 hours. The pH of the reaction mixture is then adjusted to 3 with citric acid, extracted with EtOAc and then washed with brine and water. The organic solvent is concentrated in vacuo and purified by HPLC.

[M + Na] + = 690.42

Example 107. A compound of Formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00636
X = Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

Figure 112005043726247-pct00637

Triazole-substituted fluorine precursor of the present compound was dissolved in 2 ml of xylene (xylenes) by dissolving azidoproline 100a 0.93 mmol (0.25 g) and diphenyl acetylene 1 mmol, and heated to 110 ℃ and stirred for 12 hours Prepare. The reaction mixture is separated directly by a silica column, resulting in 0.27 g of 107a (90%). [M + H] + : 449.05 0.26 g of 107b is obtained by the hydrolysis procedure described in Example 105 (99%).

The compound is then formed via the RCM procedure described in Example 1 using 107b instead of hydroxy proline.

[M + Na] + = 691.99

Example 108. A compound of Formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00638
X = n-propyl, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

108a triazole formation

4- (n-propyl) -5-phenyltriazole is prepared by Example 98 using n-propyl phenylacetylene and sodium azide.

The present compound was prepared by hydrolysis of ethyl ester through the process of Example 2, 4- (n-propyl) -5-phenyltriazole 108a according to the procedure set forth in Example 105, and thereafter, Example 106 Ready

[M + Na] + = 657.99

Example 109. A compound of Formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00639

X = m-methoxyphenyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H

109a Alkyne Formation

2- (m-methoxyphenyl) -4-methoxyphenylacetylene is prepared through the procedure of Example 99A from 4-methoxyphenylacetylene and 3-bromoanisole.

109b Triazole Formation

4- (m-methoxyphenyl) -5- (p-methoxyphenyl) triazole is prepared through the procedure of Example 3 using alkyne 109a and sodium azide.

The present compound is prepared according to the procedure described in Example 105 and subsequent to Example 106 with the present compound of Example 2 and 4- (m-methoxyphenyl) -5- (p-methoxyphenyl) triazole 109b. Prepared by hydrolysis of ethyl ester via.

[M + Na] + = 752.08

Example 110. A compound of Formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00640
X = m-bromophenyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H

110a Alkyne Formation

2- (m-bromophenyl) -4-methoxyphenylacetylene is prepared through the process of Example 99A from 4-methoxyphenylacetylene and 3-iodo-5-bromobenzene.

110b triazole formation

4- (m-bromophenyl) -5- (p-methoxyphenyl) triazole is prepared through the procedure of Example 3 using alkyne 110a and sodium azide.

The present compounds are prepared according to the procedure described in Example 105 and subsequent to Example 106 with the present compound of Example 2 and 4- (m-bromophenyl) -5- (p-methoxyphenyl) triazole 110b. Prepared by hydrolysis of ethyl ester via.

[M + Na] + = 800.05

Example 111. A compound of Formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00641

X = 1-naphthyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R3 = R4 = H

111a alkyne formation

2- (1-naphthyl) -4-methoxyphenylacetylene is prepared from the process of Example 99A from 1-iodonapthelene and 4-methoxyphenylacetylene.

111b triazole formation

4- (1-naphthyl) -5- (p-methoxyphenyl) triazole was prepared using 2- (1-naphthyl) -4-methoxyphenylacetylene 111a and sodium azide. It is prepared through the process of Example 3.

The present compounds were prepared according to the procedures described in Example 105 and subsequent thereto with the present compounds of Example 2 and 4- (1-naphthyl) -5- (p-methoxyphenyl) triazole 111b. Prepared by hydrolysis of ethyl ester via the procedure of Example 106.

[M + Na] + = 772.11

Example 112. A compound of Formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00642

X = 2-thienyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H

112a Alkyne Formation

2- (2-thienyl) -4-methoxyphenylacetylene is prepared through the process of Example 99A from 2-iodine-thiophene and 4-methoxyphenylacetylene.

112b triazole formation

4- (2-thienyl) -5- (p-methoxyphenyl) triazole was prepared through the procedure of Example 3 using 2- (2-thienyl) -4-methoxyphenylacetylene 112a and sodium azide. Ready

The present compound was prepared according to the procedure described in Example 105 and subsequent to Example 106 with the present compound of Example 2 and 4- (2-thienyl) -5- (p-methoxyphenyl) triazole 112b. Prepared by hydrolysis of ethyl ester via.

[M + Na] + = 705.31

Example 113. A compound of Formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00643

X = 3-thienyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H

113a Alkyne Formation

2- (3-thienyl) -4-methoxyphenylacetylene was prepared from the procedure of Example 99a from 2-iodine-thiophene and 4-methoxyphenylacetylene.

113b triazole formation

4- (3-thienyl) -5- (p-methoxyphenyl) triazole was prepared by the procedure of Example 3 using 2- (3-thienyl) -4-methoxyphenylacetylene 113a and sodium azide. Ready

The present compound was prepared according to the procedure described in Example 105 and subsequent to Example 106 with the present compound of Example 2 and 4- (3-thienyl) -5- (p-methoxyphenyl) triazole 113b. Prepared by hydrolysis of ethyl ester via.

[M + Na] + = 727.21

Example 114. A compound of Formula II wherein A = tBOC, G = OH, L = absent,

W =

Figure 112005043726247-pct00644

X = 4-pyrazolyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H

114a Alkyne Formation

2- (4-pyrazolyl) -4-methoxyphenylacetylene is prepared through the process of Example 99A from 4-iodopyrazole and 4-methoxyphenylacetylene.

114b triazole formation

4- (4-pyrazole) -5- (p-methoxyphenyl) triazole was prepared by the procedure of Example 3 using 2- (4-pyrazole) -4-methoxyphenylacetylene 114a and sodium azide. Ready

The title compound is the title compound of Example 2 and 4- (4-pyrazolyl) -5- (p-methoxyphenyl) triazole 114b as shown in Example 105 and subsequent ethyl ester through the process of Example 106. It is prepared by hydrolysis.

[M + H] + = 700.82.

Example 115 A = tBOC , G = OH, L = absent ,

W is

Figure 112005043726247-pct00645
Is a compound of Formula II wherein X = 3 -pyridyl , Y = p -methoxyphenyl , j = 3, m = s = 1, and R 3 = R 4 = H

115a Alkyne Formation

2- (3-pyridyl) -4-methoxyphenylacetylene is prepared from the process of Example 99A from 3-iodinepyridine and 4-methoxyphenylacetylene.

115b triazole formation

4- (3-pyridyl) -5- (p-methoxyphenyl) triazole was prepared using the procedure of Example 3 using 2- (3-pyridyl) -4-methoxyphenylacetylene 115a and sodium azide. It is manufactured through.

The title compound is the title compound of Example 2 and 4- (3-pyridyl) -5- (p-methoxyphenyl) triazole 115b followed by ethyl ester via the process shown in Example 105 and the process of Example 106. It is prepared by the hydrolysis of.

[M + H] + = 700.36.

Example 116 A = tBOC , G = OH, L = absent ,

W is

Figure 112005043726247-pct00646
And a compound of formula II wherein X = 2 -pyridyl , Y = p -methoxyphenyl , j = 3, m = s = 1, and R 3 = R 4 = H

116a alkyne formation

2- (2-pyridyl) -4-methoxyphenylacetylene is prepared from 2-iodinepyridine and 4-methoxyphenylacetylene through the procedure of Example 99A.

116b triazole formation

4- (2-pyridyl) -5- (p-methoxyphenyl) triazole was prepared through the process of Example 3 using 2- (2-pyridyl) -4-methoxyphenylacetylene 116a and sodium azide. Are manufactured.

The title compound was prepared by following the procedure shown in Example 105 as 4- (2-pyridyl) -5- (p-methoxyphenyl) triazole 116b with the title compound of Example 2 and subsequent ethyl ester through the process of Example 106. It is prepared by hydrolysis.

[M + H] + = 700.82.

Example 117 A = tBOC , G = OH, L = absent ,

W is

Figure 112007053853814-pct00647
And a compound of formula II wherein X = 2-thiazolyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H

Figure 112005043726247-pct00648

117a alkyne formation

Alkyne, 2- (2-thiazolyl) -4-methoxyphenylacetylene of the present Example, 10 ml of acetonitrile, 140 mg (0.2 mmol) of PdCl 2 (PPh 3 ) 2 and 19 mg (0.1 mmol) of Cul, Prepared by adding 4 mmol of 4-ethynylanisole, 4 mmol of 2-bromothiazole, and 1 ml of triethylamine to a degassed solution. The mixture is degassed and mixed at RT for 5 minutes and heated at 90 ° C. for 12 hours. The reaction mixture is concentrated in vacuo and purified by silica to yield 0.61 g of brown liquid in 70% yield.

Figure 112005043726247-pct00649

Figure 112005043726247-pct00650

117B triazole formation

4- (2-thiazolyl) -5- (p-methoxyfe) triazole (117d) was added to 0.3 g of a pressure tube of 117c by adding 0.74 ml of trimethylsilyl azide and 4 ml of xylene. The mixture is prepared by heating at 140 ° C. for 48 hours. The reaction mixture is separated directly by a silica column to give a brown liquid (117d) after purification (0.18 g, 50%).

Figure 112005043726247-pct00651

Figure 112005043726247-pct00652

117c ethyl ester (117e) is prepared by dissolving 0.041 mmol and 0.123 mmol of 117d of mesylate (117d) of a macrocyclic precursor in 3 ml of DMF, and adding 0.246 mmol cesium carbonate and reacting at 70 DEG C for 12 hours. . The reaction mixture is extracted with EtOAc, washed with 1M sodium bicarbonate (2 × 30 ml) and water (2 × 30 ml) and concentrated in vacuo to afford ethyl ester (117e).

[M + H] + : 734.34.

Preparation of the title compound

Figure 112005043726247-pct00653

Hydrolysis of ethyl ester 117e is accomplished by dissolving 117e in 3 ml of dioxane and adding 2 ml of 1M LiOH and stirring the resulting reaction mixture at RT for 8 hours. After the pH of the reaction mixture is adjusted to 3 with citric acid, the reaction mixture is extracted with EtOAc and washed with brine and water. The organic solution is concentrated in vacuo for purification of HPLC which yields a yellow powder (10 mg, 34% yield) after lyophilization.

Figure 112005043726247-pct00654

Example 118 A = tBOC , G = OH, L = absent , W is

Figure 112005043726247-pct00655
Is a compound of Formula II wherein X = benzyl, Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

118a alkyne formation

2- (benzyl) -2-benzylphenylacetylene is prepared from the procedure of Example 117A from 3-iodinebenzene and 3-phenyl-propyne.

118b triazole formation

4- (benzyl) -5-phenyltriazole is prepared through the process of Example 3 using 2-benzyl-1-phenylacetylene (118a) and sodium azide.

The title compound is prepared by the title compound of Example 2 and 4-benzyl-5-phenyltriazole 118b according to the process shown in Example 105 and subsequent hydrolysis of the ethyl ester via the process of Example 106.

[M + H] + = 700.82.

Example 119 A = tBOC, G = OH, L = absent,

W is

Figure 112005043726247-pct00656
And a compound of formula II wherein X = n-butyl, Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

119a triazole formation

4- (n-butyl) -5-phenyl triazole is prepared through the process of Example 3 using n-butyl-1-phenylacetylene and sodium azide.

The title compound was subjected to the subsequent hydrolysis of the title compound of Example 2 and 4- (n-butyl) -5-phenyl triazole (119a) according to the process shown in Example 105 and ethyl ester via the process of Example 106. It is prepared.

[M + H] + = 649.44.

Example 120 A = tBOC , G = OH, L = Absence, W is

Figure 112005043726247-pct00657
And a compound of formula II wherein X = n-propyl, Y = n-propyl, j = 3, m = s = 1, and R 3 = R 4 = H

120a triazole formation

4, 5- (n-propyl) triazole is prepared through the process of Example 3 using n-octin and sodium azide.

The title compound is prepared by subsequent hydrolysis of 4,5- (n-propyl) triazole 120a according to the title compound of Example 2 and the process shown in Example 105 and ethyl ester via the process of Example 106.

[M + H] + = 601.46.

Example 121 A = tBOC, G = OH, L = Absence, W is

Figure 112005043726247-pct00658
And a compound of formula II wherein X = 4- (N, N-dimethylamino) phenyl, Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

Figure 112005043726247-pct00659

121A Bromination Bromo-substituted phenyl triazole (121b) was prepared in 16 ml 1:15 MeOH / CHCl 3 by 121a (triazole 121a was prepared by the method shown in Example 2 using commercially available phenyl acetylene and sodium azide 1mmol)) is dissolved, 0.28 ml of TEA is added, and 0.128 ml of bromine is added dropwise. To the reaction mixture, 10% cold Na 2 S 2 O 5 is added until the color of the mixture disappears. The mixture is extracted with EtOAc, washed with brine and water, dried over Na 2 S0 4 and concentrated in vacuo to yield 0.216 g of 121b after purification (97%) by silica column.

[M + H] +: 224.19.

0.2 g of 121B mesylate return 121c is prepared from the purified 121b via the title compound from Example 2 via the procedure described in Example 3. [M + Na] +: 721.00

121C Suzuki Combined. Ethyl ester (121d) dissolved 121c 0.07mmol (50mg) 121c in 3ml of DME, 0.21mmol (35mg) of 4-dimethylaminophenylboric acid, 137mg of cesium carbonate, and 100mg of KF were added to this solution. It is prepared. 5 mg of Pd (PPh 3 ) 4 is added to the subsequent degassed reaction mixture. The resulting reaction mixture is heated up to 90 ° C. and mixed for 12 hours. The reaction mixture is then extracted with EtOAc, washed with brine and water, dried over Na 2 SO 4 and concentrated in vacuo to yield 40 mg (78% yield) of 121d after purification by silica column.

121D ethyl ester hydrolysis. After purification by HPLC (30%) 12 mg of 121e are prepared by the procedure described in 106 from 121d. [M + H] +: 712.33

Example 122 A = tBOC , G = OH, L = Absence, W is

Figure 112005043726247-pct00660
And a compound of formula II wherein X = (N, N-diethylamino) methyl, Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

122a triazole formation

4- (N, N-diethylaminomethyl) -5-phenyltriazole is prepared by the process of Example 3 using 3-diethylamino-1-phenylpropine and sodium azide.

The title compound was prepared by following the title compound of Example 2 and 4,-(N, N-diethylaminomethyl) -5-phenyltriazole 122a according to the process shown in Example 105 and ethyl ester via the process of Example 106. It is prepared by hydrolysis.

[M + H] + = 678.44.

Example 123 A = tBOC , G = OH, L = absent , W is

Figure 112005043726247-pct00661
And a compound of formula II wherein X = N, N -diethylaminocarbonyl , Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

123A Alkyne Formation

Figure 112005043726247-pct00662

Alkyne 123a is prepared by dissolving 10 mmol of phenylpropinoic acid, 11 mmol of BOP, and 22 mmol of DIEA in 15 ml of DMF, and adding 11 mmol of diethylamine to this solution. The resulting reaction mixture is mixed for 3 hours at RT. The reaction mixture is extracted with EtOAc (2x50ml) and washed with 1M NaHCo 3 (2x30ml), water (2x30ml), 5% citric acid (2x50ml) and brine (2x30ml). The organic extract is dried over anhydrous Na 2 SO 4 and concentrated in vacuo to yield 1.8 g (90%) of 123a. [M + H] +: 202.09

123B triazole formation

4- (N, N-diethylaminocarbonyl) -5-phenyltriazole is prepared by the process of Example 3 using 123a and sodium azide.

The title compound is prepared by following the title compound of Example 2 and 4- (N, N-diethylaminocarbonyl) -5-phenyltriazole (123b) according to the process shown in Example 105 and the ethyl ester via the process of Example 106. It is prepared by hydrolysis.

[M + H] + = 692.47

Example 124 A = tBOC, G = OH, L = absence, W is

Figure 112007053853814-pct00663
And a compound of formula II wherein X = m-chlorophenyl, Y = 4-ethoxyphenyl, j = 3, m = s = 1, and R 3 = R 4 = H

124a Alkyne Formation

2- (m-chlorophenyl) -4-ethoxyphenylacetylene is prepared from 3-chloro-bromobenzene and 4-ethoxyphenylacetylene through the procedure of Example 99.

124b triazole formation

4- (m-chlorophenyl) -5- (p-ethoxyphenyl) triazole was prepared in Example 3 using 2- (m-chlorophenyl) -4-ethoxyphenylacetylene (124a) and sodium azide. Is prepared.

The title compound was followed by 4- (m-chlorophenyl) -5- (p-ethoxyphenyl) triazole (124b) according to the title compound of Example 2 and the process shown in Example 105 and ethyl ester via the process of Example 106. It is prepared by the hydrolysis of.

[M + H] + = 747.37.

Example 125 A = tBOC, G = OH, L = absent, W is

Figure 112007053853814-pct00664
And a compound of formula II wherein X = 2-phenylethenyl, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

The title compound is formulated by the Suzuki reaction described in Example 121 from 121c with subsequent hydrolysis following the process shown in Example 106 with phenylethenylboronic acid.

[M + H] + = 695.30.

Example 126 A compound of formula II wherein A = tBOC, G = OH, L = absent, W is 5,6-methylbenzotriazole, j = 3, m = s = 1, and R 3 = R 4 = H

The title compound is prepared by the title compound of Example 2, 5,6-methylbenzotriazole according to the process shown in Example 105, and subsequent hydrolysis of ethyl ester via the process of Example 106.

[M + H] + = 595.42.

Example 127 A = tBOC, G = OH, L = absent,

W is

Figure 112005043726247-pct00665
Is a compound of Formula II wherein X = N -ethylaminocarbonyl , Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

127a alkyne formation

Figure 112005043726247-pct00666

Alkyne 127a is prepared by dissolving 10 mmol of phenylpropinoic acid, 11 mmol of BOP, and 22 mmol of DIEA in 25 ml of DMF, and adding 11 mmol of ethylamine to this solution. The resulting reaction mixture is mixed for 3 hours at RT. The reaction mixture is extracted with EtOAc (2x50ml) and washed with 1M NaHCo 3 (2x30ml), water (2x30ml), 5% citric acid (2x50ml) and brine (2x30ml). The organic extract is dried over anhydrous Na 2 SO 4 and concentrated in vacuo to yield 1.8 g (90%) of 127a. [M + H] +: 177.09

127B triazole formation

4- (N-ethylaminocarbonyl) -5-phenyltriazole is prepared by the process of Example 3 using 127a and sodium azide.

The title compound was subjected to subsequent hydrolysis of 4- (N-ethylaminocarbonyl) -5-phenyltriazole (127b) and ethyl ester via the process of Example 106 according to the title compound of Example 2 and the process shown in Example 105. It is prepared.

Example 128 A =-(C = O) -OR 1 , R 1 = cyclopentyl, G = OH, L = absent, W is

Figure 112007053853814-pct00667
And a compound of formula II wherein X = N-ethylaminocarbonyl, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

128a-amine deprotection

0.041 mmol of the title compound of Example 105 is dissolved in 4 ml of HCldml 4M solution in dioxane and mixed for 1 hour. Reaction residue 128a is concentrated in vacuo.

128b-Chloroformate Reagent

The chloroformate reagent 128b is prepared by dissolving 0.045 mmol of cyclopentanol in THF (3 ml) and 0.09 mmol of phosgene in toluene (20%). The resulting reaction mixture is mixed for 2 hours at room temperature and the solvent is removed in vacuo. DCM was added to the residue, which was subsequently dried twice in vacuo and concentrated to give chloroformate reagent 128b.

128c-carbamate formation

The title carbamate is prepared by dissolving the residue 128a in 1 ml THF, adding 0.045 mmol of TEA, and cooling the resulting reaction mixture to 0 ° C. To this 0 ° C. reaction mixture, 3 ml of chloroformate reagent 128b of THF is added. The resulting reaction mixture is reacted at 0 ° C. for 2 hours, extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO 4 , concentrated in vacuo and dried. The natural composition is purified by silica column and the ethyl ester is subsequently hydrolyzed by the process shown in Example 106d.

Example 129 A =-(C = O) -OR 1 , R 1 = cyclobutyl, G = OH, L = absent,

W is

Figure 112005043726247-pct00668
And a compound of formula II wherein X = phenyl , Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

The title compound is prepared by the method described in Example 33 with the title compound and cyclobutanol of Example 105, followed by ethyl ester hydrolysis by the process shown in Example 106.

Example 130 A =-(C = O) -OR 1 , R 1 = cyclohexyl, G = OH, L = absent,

W is

Figure 112005043726247-pct00669
Of formula II wherein X = phenyl , Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

The title compound is prepared by the method of Example 33 together with the title compound of Example 105 and cyclohexanol, followed by ethyl ester hydrolysis by the process shown in Example 106.

Example 131 A =-(C = O) -OR 1 and R 1 =

Figure 112007053853814-pct00670
, G = OH, L = absent, W is
Figure 112007053853814-pct00671
And a compound of formula II wherein X = phenyl, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

The title compound is prepared by hydrolysis of ethyl ester by the method of Example 33 together with the title compound of Example 105 and (R) -3-hydroxytetrahydrofuran, followed by the process shown in Example 106.

Example 132 A =-(C = O) -OR 1 and R 1 =

Figure 112007053853814-pct00672
, G = OH, L = absent, W is
Figure 112007053853814-pct00673
And a compound of formula II wherein X = phenyl, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

The title compound is prepared by hydrolysis of ethyl ester by the method of Example 33 together with the title compound of Example 105 and (S) -3-hydroxytetrahydrofuran, followed by the process shown in Example 106.

Example 133 A =-(C = O) -OR 1 and R 1 =

Figure 112007053853814-pct00674
, G = OH, L = absent,

W is

Figure 112005043726247-pct00675
And a compound of formula II wherein X = phenyl , Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

The title compound is combined with the title compound of Example 105

Figure 112005043726247-pct00676
And by hydrolysis of ethyl ester by the method of Example 33, followed by the process shown in Example 106.

Example 134 A =-(C = O) -OR 1 , R 1 = chloropentyl, G = OH, L = absent,

W is

Figure 112005043726247-pct00677
And a compound of formula II wherein X = phenyl , Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

The title compound is prepared by dissolving 0.041 mmol of the title compound from Example 105 in 4 ml of a 4M solution of HCl in dioxane and mixing the reaction mixture for 1 hour. To this residue, 4 ml of THF and 0.045 mmol of TEA are added and the mixture is cooled to 0 ° C., to which 0.045 mmol of cyclopental acid chloride is added. The resulting reaction mixture is mixed at 0 ° C. for 2 hours. The reaction mixture is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO 4 , concentrated in vacuo and dried. The natural composition is purified by silica column and the ethyl ester is subsequently hydrolyzed by the process shown in Example 106.

Example 135 A =-(C = O) -NH-R 1 , R 1 = chloropentyl, G = OH, L = absent,

W is

Figure 112005043726247-pct00678
And a compound of formula II wherein X = phenyl , Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

The title compound is prepared by dissolving 0.041 mmol of the title compound from Example 105 in 4 ml of a 4M solution of HCl in dioxane and mixing for 1 hour. The resulting reaction residue is concentrated in vacuo, dissolved in 4 ml THF and cooled to 0 ° C. To the 0 ° C. solution, 0.045 mmol of cyclopental isocyanate is added. The solution is then extracted with EtOAc, washed with 1% HCl, water and brine, dried over MgSO 4 , concentrated in vacuo and dried. The natural composition is purified by silica column and the ethyl ester is subsequently hydrolyzed by the process shown in Example 106.

Example 136 A =-(C = S) -NH-R 1 , R 1 = chloropentyl, G = OH, L = absent,

W is

Figure 112005043726247-pct00679
And a compound of formula II wherein X = phenyl , Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

The title compound is prepared by dissolving 0.041 mmol of the title compound from Example 105 in 4 ml of a 4M solution of HCl in dioxane and mixing for 1 hour. The resulting reaction residue is concentrated in vacuo, dissolved in 4 ml THF and cooled to 0 ° C. To the 0 ° C. solution, 0.045 mmol of cyclopentyl isothiocyanate is added and the resulting reaction mixture is mixed at RT for 4 h. The solution is then extracted with EtOAc, washed with 1% HCl, water and brine, dried over MgSO 4 , concentrated in vacuo and dried. The natural composition is purified by silica column and the ethyl ester is subsequently hydrolyzed by the process shown in Example 106.

Example 137 A = -S (O) 2 -R 1 , R 1 = chloropentyl, G = OH, L = absent,

W is

Figure 112005043726247-pct00680
And a compound of formula II wherein X = phenyl , Y = phenyl , j = 3, m = s = 1, and R 3 = R 4 = H

The title compound is prepared by dissolving 0.041 mmol of the title compound from Example 105 in 4 ml of a 4M solution of HCl in dioxane and mixing for 1 hour. 0.045 mmol of TEA is added to the resulting concentrated reaction residue that was dissolved in 4 ml THF and cooled to 0 ° C. To the 0 ° C. solution 0.045 mmol of cyclopentyl sulphonyl chloride is added and the resulting reaction mixture is mixed at 0 ° C. for 2 hours. The solution is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO 4 , concentrated in vacuo and dried. The natural composition is purified by silica column and the ethyl ester is subsequently hydrolyzed by the process shown in Example 106.

Example 138 A =-(C = O) -OR 1 , R 1 = chloropentyl, G = -O-phenethyl, L = absent, W is

Figure 112007053853814-pct00681
And a compound of formula II wherein X = phenyl, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

Figure 112005043726247-pct00682

The title compound was prepared by addition to a solution of the title compound of Example 128, and 1.2eq PyBrOP, 4eq. In phenethyl alcohol (138a) in 0.5ml DCM. 0 ° C. is added to a solution of catalytic amounts of DIEA and DMAP. The resulting reaction mixture was mixed at 0 ° C. for 1 hour and then warmed at RT for 4-12 hours. The reaction mixture was purified by silica gel flash chromatography using different ratios of hexanes: EtOAc (9: 1-> 5: 1-> 3: 1-> 1: 1) as suspension to give the title compound isolate. Produces phenethyl ester 138b. Other esters can be formed using the same process.

Example 139 A =-(C = O) -OR 1 , R 1 = chloropentyl, G = -NH-phenethyl, L = absent, W is

Figure 112007053853814-pct00683
And a compound of formula II wherein X = phenyl, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

Figure 112005043726247-pct00684

The title compound is prepared by adding to a solution of the title compound of Example 128, and 0.5 ml DMF of phenethylamine (139a) (0.05 ml), EDC (1.2 eq.) And DIEA (4 eq) are added at 0 ° C. The resulting reaction mixture is mixed for 1 hour. Subsequently, the reaction is warmed for 4-12 hours at RT. The reaction mixture was purified by silica gel flash chromatography using different ratios of hexanes: EtOAc (9: 1-> 5: 1-> 3: 1-> 1: 1) as suspension to give the title compound phenethyl amide. Produce 139b. Other amides can be formed using the same process.

Example 140 A =-(C = O) -OR 1 , R 1 = cyclopentyl, G = -NHS (O) 2 -pentethyl, L = absent, W is

Figure 112007053853814-pct00685
And a compound of formula II wherein X = phenyl, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

Figure 112005043726247-pct00686

The title compound was prepared by addition to a solution of the title compound of Example 128, and α-toluenesulfonamide (140a) (10 mg), 1.2eq. In 0.5 ml DCM. PyBrOP, 4eq. The catalytic amount of DIEA and DMAP is added at 0 ° C. The resulting reaction mixture was mixed for 1 hour and then warmed at RT for 4-12 hours. The reaction mixture was purified by silica gel flash chromatography using different ratios of hexanes: EtOAc (9: 1-> 5: 1-> 3: 1-> 1: 1) as suspension to give the title compound sulfonamide ( 140b).

Other sulfonamides can be formed using the same process.

Example 141 A =-(C = O) -OR 1 , R 1 = cyclopentyl, G =-(C = O) -OH, L = absent, W is

Figure 112007053853814-pct00687
And a compound of formula II wherein X = phenyl, Y = phenyl, j = 3, m = s = 1, and R 3 = R 4 = H

Figure 112005043726247-pct00688

The title compound is prepared by addition to a solution of the title compound of Example 128, wherein α-hydroxy-α-methyl-propionitrile (0.1 ml) and the amount of TFA catalyst are added at 0 ° C. The resulting reaction mixture is warmed from 0 ° C. to RT over 4-12 hours and hydrolyzed to concentrated hydrochloric acid of dioxane.

The reaction is then extracted with EtOAc and washed with water and brine to yield an alpha hydroxy compound 141a in crude form. This crude compound 141a becomes a Dess-Martin oxide in THF (0.5 mL) provided with an alpha carbonyl compound 141b in a crude form. Crude 141b is an elution phase (9: 1 → 5: 1 → 3: 1 → 1: 1) with silica gel flash chromatography using different ratios of hexanes: EtOAc. Purified by gel flash chromatography to provide an isolated keto acid (141b) of the present compound.

Example 142. A compound of formula II wherein A =-(C = O) -OR 1 , R 1 = cyclopentyl, G =-(C = O) -O-phenethyl, L = Absent, W is

Figure 112009026180213-pct00689
, X = phenyl, Y = phenyl, j = 3, m = s = 1, R 3 = R 4 = H.

This compound is prepared with the keto acid of the present compound of Example 141 and phenethanol by the process described in Example 138.

Example 143. A compound of formula II wherein A =-(C = O) -OR l , R 1 = cyclopentyl, G =-(C = O) -NH-phenethyl, L = Absent, W is

Figure 112009026180213-pct00690
, X = phenyl, Y = phenyl, j = 3, m = s = 1, R 3 = R 4 = H.

This compound is prepared with the keto acid of the present compound of Example 141 and phenethyl amine by the process described in Example 139.

Example 144. A compound of Formula II wherein A =-(C = O) -OR l , R 1 = cyclopentyl, G =-(C = O) -NH-S (O) 2 -benzyl ( benzyl), L = absent, W is

Figure 112009026180213-pct00691
, X = phenyl, Y = phenyl, j = 3, m = s = 1, R 3 = R 4 = H.

This compound is prepared with the keto acid of the present compound of Example 141 and alpha toluenesulfonamide by the process described in Example 140.

Example 145. A compound of Formula II wherein A = tBOC, G = OH, L =-(C = O) CH 2- , W is

Figure 112009026180213-pct00692
, X = phenyl, Y = phenyl, j = 1, m = s = 1, R 3 = R 4 = H.

The compound was prepared using the modified cyclic peptide precursor mesylate and 4,5 diphenyltriazole produced in Example 88C by the substitution method described in Example 105. And hydrolysis of the ethyl ester via the method described in Example 106.

Example 146. A compound of Formula II wherein A = tBOC, G = OH, L = -CH (CH 3 ) CH 2- , W is

Figure 112009026180213-pct00693
, X = phenyl, Y = phenyl, j = 1, m = s = 1, R 3 = methyl, R 4 = H.

This compound was prepared using the modified cyclic peptide precursor mesylate and 4,5 diphenyltriazole produced in Example 89G by the substitution method described in Example 105, followed by Example Hydrolysis of the ethyl ester is carried out via the method described in 106.

Example 147. A compound of Formula II wherein A = tBOC, G = OH, L = -O-, W is

Figure 112009026180213-pct00694
, X = phenyl, Y = phenyl, j = 0, m = s = 1, R 3 = methyl, R 4 = hydrogen.

This compound is prepared using the modified cyclic peptide precursor mesylate and 4,5 diphenyltriazole produced in Example 90D by the substitution method described in Example 105, followed by Example Hydrolysis of the ethyl ester is carried out via the method described in 106.

Example 148. A compound of Formula II wherein A = tBOC, G = OH, L = -S-, W is

Figure 112009026180213-pct00695
, X = phenyl, Y = phenyl, j = 0, m = s = 1, R 3 = methyl, R 4 = hydrogen

The compound was prepared with the modified cyclic peptide precursor mesylate and 4,5 diphenyltriazole produced in Example 91E by the substitution method described in Example 105, followed by Example 106. Hydrolysis of the ethyl ester is carried out through the method described in.

Example 149. A compound of Formula II wherein A = tBOC, G = OH, L = -S (O)-, W is

Figure 112009026180213-pct00696
, X = phenyl, Y = phenyl, j = 2, m = s = 1, R 3 = methyl, R 4 = hydrogen

This compound was prepared with the modified cyclic peptide precursor mesylate and 4,5 diphenyltriazole produced in Example 92B by the substitution method described in Example 105, followed by Example 106. Hydrolysis of the ethyl ester is carried out through the method described in.

Example 150. A compound of Formula II wherein A = tBOC, G = OH, L = -S (O) 2- , W is

Figure 112009026180213-pct00697
, X = phenyl, Y = phenyl, j = 2, m = s = 1, R 3 = methyl, R 4 = H

The compound was prepared with the modified cyclic peptide precursor mesylate and 4,5 diphenyltriazole produced in Example 93B by the substitution method described in Example 105, followed by Example 106. Hydrolysis of the ethyl ester is carried out through the method described in.

Example 151. A compound of Formula II wherein A = tBOC, G = OH, L = -SCH 2 CH 2- , W is

Figure 112009026180213-pct00698
, X = phenyl, Y = phenyl, j = 0, m = s = 1, R 3 = R 4 = CH 3

Figure 112005043726247-pct00699

151A. Synthesis of (S) -N-Boc-2-amino (amino) -3-methyl-3 (1-mercapto-4-butenyl) butanoic acid (151b)

L-Penicillamine (151a) is dissolved in DMF / DMSO (5: 1), and then 4-bromopentene and CsOH.H 2 O are added to the mixture and additionally 2 Stirring is performed for a time. The DMF is then removed in vacuo and the remaining mixture is diluted with 0.5N HCl to pH 4-5. Then extracted with two portions of EtOAc. The organic phase is washed with brine (2 ×) and dried over MgSO 4 , and the dried product is evaporated to give crude carboxylic acid 151b.

151B. Synthesis of Modified Cyclic Peptide Precursor Mesylate

Modified cyclic peptide precursor mesylate is synthesized as described in Example 1 using modified amino acid 151b instead of Boc-L-2-amino-8-nonenoic acid (1a). It is manufactured using the process. This is then converted to the corresponding mesylate via the method detailed in Example 2.

This compound was prepared with the modified cyclic peptide precursor mesylate and 4,5 diphenyltriazole produced in Example 151B by the substitution method described in Example 105, followed by Example 106. Hydrolysis of the ethyl ester is carried out through the method described in.

Example 152. The compound of formula II wherein A = tBOC, G = OH, L = CF 2 CH 2 , W

Figure 112009026180213-pct00700
, X = phenyl, Y = phenyl, j = 1, m = s = 1, R 3 = R 4 = H

The compound was prepared with the modified cyclic peptide precursor mesylate and 4,5 diphenyltriazole produced in Example 95C by the substitution method described in Example 105, followed by Example 106. Hydrolysis of the ethyl ester is carried out through the method described in.

Example 153. A compound of Formula II wherein A = tBOC, G = OH, L = -CHFCH 2- , W is

Figure 112009026180213-pct00701
, X = phenyl, Y = phenyl, j = 1, m = s = 1, R 3 = R 4 = H

This compound was prepared with the modified cyclic peptide precursor mesylate and 4,5 diphenyltriazole produced in Example 96C by the substitution method described in Example 105, followed by Example 106. Hydrolysis of the ethyl ester is carried out through the method described in.

Example 154. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112009026180213-pct00702
, X = phenyl, Y = phenyl, j = 3, m = s = 1, R 3 = R 4 = H

154A. Saturated cyclic peptide precursor mesylate is prepared by catalytic reduction of mesylate cyclic peptide precursor 2 with Pd / C in MeOH in the presence of H 2 .

This compound was prepared with the saturated cyclic peptide precursor mesylate and 4,5 diphenyltriazole produced in Example 154A by the substitution method described in Example 105, followed by Example 106. Hydrolysis of the ethyl ester is carried out through the method described in.

Example 155. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112009026180213-pct00703
j = 3, m = s = 1, R 3 = R 4 = H

155A. Formation of Substituted Benzotriazoles

Figure 112005043726247-pct00704

The bromo-substituted benzotriazole (155b) of this embodiment is 5-bromo-3, 4-dimethylbenzene-1, 2-diamine (2 diamine), 1.15 mL (20 mmol) of glacial acetic acid and 10 mL of water are combined, and the resulting mixture is heated to obtain a clear solution. The clear solution is then cooled to 5 ° C. and 5 ml of water and a cold solution of 0.83 g (12 mmol) of sodium nitrite are added. The reaction mixture is then heated at 70-80 ° C. for 2 hours. The reaction mixture is then extracted with EtOAc and washed with brine and water. It is then dried over Na 2 SO 4 and concentrated in vacuo. This crude product is purified by a silica column.

155B. substitution

Figure 112005043726247-pct00705

The ethyl ester 155c has the present compound of Example 2 and bromo-substituted benzotriazole 155b, and is produced by the substitution method described in Example 105.

The compound is finally prepared by the hydrolysis process described in Example 106 with ethyl ester 155c.

Example 156. A compound of Formula II wherein A = tBOC, G = OH, L = absent,

W is

Figure 112009026180213-pct00706
, j = 3, m = s = 1, R 3 = R 4 = H

156A. Suzuki Reaction

Figure 112005043726247-pct00707

The compound 156a of this example is prepared through the Suzuki coupling reaction with 3-thienyl boronic acid described in 155c and Example 26C.

156B. Hydrolysis

The compound is prepared through the hydrolysis process described in Example 106 with ethyl ester 156a.

Example 157. A compound of Formula II wherein A = tBOC, G = OH, L = absent, W is

Figure 112009026180213-pct00708
, j = 3, m = s = 1, R 3 = R 4 = H

157a. Formation of Bicyclic Compounds

The bicyclic compound of the present invention is prepared as 2,3-diaminopyridine by the treatment of Example 157A.

The title compound is prepared from the bicyclic compound prepared in 157a and the title compound of Example 2 by hydrolysis of the ethyl ester through the treatment of Example 106 followed by an alternative method described in Example 105.

Example 158. A compound of Formula IV wherein A = tBOC, G = OEt, L = absent, X = Y = bromine, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen.

To a mixture of macrocyclic compound (1) (185 mg, 0.38 mmol) and THP (5 mL) of 4,5-dibrom-2H-pyridazin-3-one (95 mg, 0.38 mmol), DIAD (148 μl, 0.075) mmol) is added at 0 ° C. in the form of drops. After mixing for 15 minutes at 0 ° C., the solution is brought to room temperature and stirred for further 16 hours. The mixture is then concentrated in vacuo and the residue is purified by column chromatography eluting with 40% ethyl acetate-hexanes to give 235 mg (86%) of the title compound.

1 H-NMR (500 MHz, CDCI3) 8 (ppm): 7.8 (s, 1H), 7.1 (brs, 1H), 5.5 (m, 2H), 5.2 (m, 2H), 5.0 (m, 1H), 4.4 (brt, 1 H), 4.0-4. 2 (m, 4H), 2.9 (m, 1H), 2.6 (m, 1H), 1.8-2. 3 (m, 5H), 1.4 (s, 9H), 1.2 (t, 3H). [M + H] + = 730.6.

Example 159. A = tBOC, G = OEt, L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen Compound of IV.

Round a mixture of the title compound (40 mg, 0.055 mmol), 3-thiophene bromic acid (35 mg, 0.28 mmol), cesium carbonate (71 mg, 0.22 mmol), potassium fluoride monohydrate (41 mg, 0.44 mmol) in Example 158 Place in the bottom flask and wash twice with nitrogen. DME is added to this mixture and washed again with nitrogen before adding palladium tetrakis (triphenylphosphine) (7 mg, 10 mol%). After two more washes with nitrogen, the mixture is refluxed by heating to reflux for 20 hours. The mixture is then cooled, diluted in water and extracted three times with EtOAc. The combined EtOAc layer is washed once with brine, dried (MgSO 4 ) and concentrated in vacuo. The residue is purified by column chromatography eluting with 20-40% EtOAc-hexanes to give the title compound as a clean membrane (24 mg, 60%).

1 H-NMR (500 MHz, CDCI3) # (ppm): 7.9 (s, 1H), 7.6 (s, 1H), 7.3 (s, 1H), 7.3 (m, 1H), 7.0 (s, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 5.7 (m, 1H), 5.5 (m, 1H), 5.4 (brd, 1H), 5.2 (t, 1H), 5.0 (m, 1H), 4.6 (brt, 1 H), 4.0-4. 2 (m, 4H), 2.9 (m, 1H), 2.6 (m, 1H), 2.0-2. 3 (m, 5H), 1.4 (s, 9H), 1.2 (t, 3H). [M + Na] < + > = 758.63.

Example 160. Formula wherein A = tBOC, G = OH, L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen Compound of IV.

To a solution of the title compound (24 mg, 0.033 mmol) in Example 159 of THF / MeOH / H 20 (2/1 / 0.5 mL), lithium hydroxide (14 mg, 0.33 mmol) is added. After 16 hours of mixing at room temperature, the mixture is oxidized to citric acid to pH 4 and extracted three times with EtOAc. The combined organic extracts are washed once with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 5-10% methanol-chloroform to give the title compound (13 mg, 56%).

[M + H] + = 708.3

Example 161. A compound of Formula IV wherein A = tBOC, G = OH, L = absent, X = Y = phenyl, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen.

The title compound was subjected to double Suzuki coupling the phenyl boric acid with the title compound of Example 158 following the treatment of Example 159 following hydrolysis of the ethyl ester via the method described in Example 160. Is manufactured by.

[M + H] + = 696.40

Example 162. A = tBOC, G = OH, L = absent, X = Y = 4- (N, N-dimethylamino) phenyl, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = Compound of formula II wherein hydrogen .

The title compound was prepared by coupling the title compound of Example 158 with 4- (N, N-dimethylamino) phenylboric acid following the treatment of Example 159 following hydrolysis of the ethyl ester via the method described in Example 160. It is made by double Suzuki.

[M + H] + = 782.30

Example 163. A = tBOC, G = OH, L = absent, X = Y = 4- (trifluoromethoxy) phenyl, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = Compound of formula II being hydrogen .

The title compound was coupled to 4- (trifluoromethoxy) phenylboric acid and the title compound of Example 158 following the treatment of Example 159 following hydrolysis of the ethyl ester via the method described in Example 160. Is manufactured by double Suzuki.

[M + H] + = 864.09

Example 164. A = tBOC, G = OH, L = absent, X = Y = 4- (methanesulfonyl) phenyl, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen Compound of Phosphorus II .

The title compound was subjected to coupling of the title compound of Example 158 with 4- (methanesulfonyl) phenylboric acid following the treatment of Example 159 following hydrolysis of the ethyl ester via the method described in Example 160. It is manufactured by double Suzuki.

Example 165. A = tBOC, G = OH, L = absent, X = Y = 4- (cyano) phenyl, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen Compound of Formula II .

The title compound was double-coupled with 4- (cyano) phenylboric acid and the title compound of Example 158 following the treatment of Example 159 following hydrolysis of the ethyl ester via the method described in Example 160. It is manufactured by double Suzuki.

[M + H] + = 746.14

Example 166. Formula wherein A = tBOC, G = OH, L = absent, X = Y = pyrid-3-yl, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen II compound .

The title compound was subjected to double Suzuki coupling between 3-pyridyl boric acid and the title compound of Example 158 following the treatment of Example 159 following hydrolysis of the ethyl ester via the method described in Example 160. Suzuki).

[M + H] + = 698.3

Example 167. A = tBOC, G = OH, L = absent, X = Y = 4- (morphonyl-4-yl-methanonyl) phenyl, Z = hydrogen, j = 3, m = s = 1, A compound of formula II wherein R 3 = R 4 = hydrogen .

The title compound was used with 4-carboxyphenyl boric acid and the title compound of Example 158 following the method described in Example 159 following morpholine and amide formation, under standard amide bond formation conditions such as PyBrOP, DIEA, DMAP, etc. of DMF. It is produced by double Suzuki coupling. The ethyl ester of the resulting compound is then hydrolyzed via the hydrolysis treatment of Example 160.

Example 168. Formula II wherein A = tBOC, G = OH, L = absent, X = bromo, Y = methoxy, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen Compound of .

The title compound is prepared from the title compound of Example 158 via hydrolysis of ethyl esters according to the treatment described in Example 160, but in addition to hydrolysis of ethyl esters, addition of methoxy at position 5 is observed.

[M + H] + = 652.2, 654.2

Example 169 Formula wherein A = tBOC, G = OH, L = absent, X, Y both = phenyl, Z = 4-methoxyphenyl, j = 3, m = s = 1, R 3 = R 4 = hydrogen II compound .

In combination with commercially available 4- (4-methoxy-phenyl) -2H-phthalazin-1-one, the hydrolysis of ethyl esters was carried out in the Mitsunobu state as defined in Method 20, and then via the treatment of Example 160. Are manufactured accordingly.

[M + H] + = 700.1

Example 170. Formula II wherein A = tBOC, G = OH, L = absence, X, Y both = phenyl, Z = 4-chlorophenyl, j = 3, m = s = 1, R 3 = R 4 = hydrogen Compound of .

With the commercially available 4- (4-chloro-phenyl) -2H-phthalazin-1-one, the Mitsunobu state set forth in Method 20, followed by hydrolysis of the ethyl ester through the treatment of Example 160 Are manufactured.

[M + H] + = 704.2

Example 171. A = tBOC, G = OH, L = absent, X = 4-fluorophenyl, Y = hydrogen, Z = phenyl, j = 3, m = s = 1, R 3 = R 4 = hydrogen Compound of Formula II .

With the commercially available 4- (4-fluoro-phenyl) -6-phenyl-2H-pyridazin-3-one, the Mitsunobu state as defined in Method 20, followed by the treatment of Example 160 It is prepared according to hydrolysis.

[M + H] + = 704.2

Example 172. A = tBOC, G = OH, L = absent, X = hydrogen, Y = 1-piperidyl, Z = phenyl, j = 3, m = s = 1, R 3 = R 4 = hydrogen Compound of Formula II .

With the commercially available 6-phenyl-5-piperidin-1-yl-2H-pyridazin-3-one, the Mitsunobu state set forth in Method 20 and then the ethyl ester via the treatment of Example 160 It is prepared according to hydrolysis.

[M + H] + = 702.3

Example 173. Formula II wherein A = tBOC, G = OEt, L = absent, X = hydrogen, Y = bromo, Z = phenyl, j = 3, m = s = 1, R 3 = R 4 = hydrogen Compound .

Along with the commercially available 5-bromo-6-phenyl-2H-pyridazin-3-one, it is prepared according to the Mitsunobu state defined in Method 20.

[M + H] + = 726.3, 728.3

Example 174 A = tBOC, G = OH, L = absent, X = hydrogen, Y = thiophen-3-yl, Z = phenyl, j = 3, m = s = 1, R 3 = R 4 = hydrogen Compound of Phosphorus II .

The title compound is prepared with thiophen-3-yl boric acid and the title compound of Example 173 following hydrolysis of the ethyl ester via the method described in Example 160, according to the Suzuki coupling state described in Example 159. .

[M + H] + = 730.3

Example 175 A = tBOC, G = OEt, L = absent, X = bromo, Y = 1-pyrrolidyl, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen Compound of Phosphorus II .

In 2 mL of acetonitrile, a mixture of the title compound of Example 158 (45 mg, 0.062 mmol), pyrrolidine (21 mL, 0.25 mmol), potassium carbonate (34 mg, 0.25 mmol) was heated to reflux for 3 hours. After cooling to room temperature, the mixture is filtered through a sintered glass funnel and concentrated in vacuo. The residue is redissolved in ethyl acetate, washed once with saturated sodium carbonate, washed once with brine, dried (MgSO 4 ), filtered, concentrated in vacuo and chromatographed on silica gel eluting with 3% methanol-chloroform. Obtained yellow residue is obtained, 37 mg (83%) of the title compound.

[M + H] + = 719.2, 721.2

Example 176. A = tBOC, G = OH, L = absence, X = thiophen-3-yl, Y = 1-pyrrolidyl, Z = hydrogen, j = 3, m = s = 1, R 3 = A compound of formula IV wherein R 4 = hydrogen.

The title compound is prepared with the title compound of Example 175 and thiophen-3-yl boric acid using the Suzuki state described in Example 159 after hydrolysis of the ethyl ester according to the method of Example 160.

[M + H] + = 694.3

Example 177 Formula IV wherein A = tBOC, G = OEt, L = absence, X = Bromo, Y = Azido, Z = Hydrogen, j = 3, m = s = 1, R 3 = R 4 = Hydrogen IV Of compounds.

In 2 mL of acetonitrile, a mixture of the title compound of Example 158 (45 mg, 0.062 mmol), sodium azide (16 mg, 0.25 mmol), potassium carbonate (34 mg, 0.25 mmol) was heated to reflux for 3 hours. After cooling to room temperature, the mixture is filtered through a sintered glass funnel and concentrated in vacuo. The residue is redissolved in ethyl acetate, washed once with saturated sodium carbonate, washed once with brine, dried (MgSO 4 ), filtered, concentrated in vacuo and chromatographed on silica gel eluting with 3% methanol-chloroform. Obtained yellow residue is obtained, 37 mg (83%) of the title compound.

Example 178. A = tBOC, G = OEt, L = absence, X = thiophen-3-yl, Y = azido, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = Compound of formula IV which is hydrogen .

The title compound is prepared from the title compound of Example 177 and thiophen-3-yl boric acid using the Suzuki state described in Example 159.

Example 179. A = tBOC, G = OH, L = absence, X = thiophen-3-yl, Y = azido, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = Compound of formula II being hydrogen .

The title compound is prepared by hydrolysis of the ethyl ester of the title compound of Example 178 via the hydrolysis treatment of Example 160.

Example 180 A = tBOC, G = OH, L = absent, X = thiophen-3-yl, Y = tetrazol-2-yl, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen compound of the formula II.

To a solution of the title compound (2.63 mmol) of Example 178 in toluene (8 ml), KCN (10.53 mmol) and Et 3 N.HCl (10.53 mmol) are added. The mixture is heated at 115 ° C. for 18 h, diluted with DCM, washed with 5% citric acid (solution), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to give crude in the form of the title compound. Obtain ethyl ester. Hydrolysis of the ethyl ester is carried out via the method described in Example 160 to give a compound.

Example 181 A = tBOC, G = OH, L = absent, X = Y = mercapto-2-pyrimidine, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen Compound of Formula II .

Figure 112005043726247-pct00709

In 2 mL of acetonitrile, a mixture of the title compound of Example 158 (45 mg, 0.062 mmol), pyrimidine-2-thiol (0.25 mmol) and potassium carbonate (34 mg, 0.25 mmol) was heated to reflux for 3 hours. After cooling to room temperature, the mixture is filtered through a sintered glass funnel and concentrated in vacuo. The residue is redissolved in ethyl acetate, washed once with saturated sodium carbonate, washed once with brine, dried (MgSO 4 ), filtered, concentrated in vacuo and chromatographed on silica gel eluting with 3% methanol-chloroform. Obtained yellow residue is obtained and 181b in 19% yield. Ethyl ester 181b of the mixture is hydrolyzed via the method described in Example 160 to afford the title compound.

[M + H] + = 764.3

Example 182. A = tBOC, G = OH, L = absence, X = bromo, Y = mercapto-2-prilimidine, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = Compound of formula II wherein hydrogen .

The title compound is prepared by the hydrolysis of ethyl ester 181a of the mixture formed in Example 181 via the method of Example 160.

[M + H] + = 732.2, 734.2

Example 183. A = tBOC, G = OH, L = absence, X = thiophen-3-yl, Y = mercapto-2-prilimidine, Z = hydrogen, j = 3, m = s = 1, A compound of formula II wherein R 3 = R 4 = hydrogen .

The title compound is prepared with thiophen-3-yl boric acid from compound 181a from Example 181 after the hydrolysis of the ethyl ester via the method described in Example 160, according to the Suzuki coupling state of Example 159.

Example 184. Formula wherein A = tBOC, G = OEt, L = absent, X = Y = thiazol-2-yl, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen II compound .

To the degassing solution of Example 158 (1 mmol) and thiazol-2-yl (2 mmol), Pd (PPh 3 ) 4 (10 mol%) is added. The mixture is degassed two more times with nitrogen and heated to 100 ° C. for 3 hours. The cooled mixture is concentrated in vacuo and the residue is purified by column chromatography eluting with 30% EtOAc / hexanes after hydrolysis of the ethyl ester via the method of Example 160 to afford the title compound.

[M + H] + = 710.3

Example 185. Formula wherein A = tBOC, G = OH, L = absent, X = Y = imidazol-1-yl, Z = hydrogen, j = 3, m = s = 1, R 3 = R 4 = hydrogen II compound .

The title compound was dried, under nitrogen dioxane, of the title compound (0.068 mmol), imidazole (2eq), Cs 2 CO 3 (3eq), exophos (30 mol%), Pd (OAc) 2 from Example 158. Prepared by adding to the mixture. The reaction mixture is then degassed and stirred at 75 ° C. for 18 hours. Upon completion of the reaction, while monitoring via TLC, the reaction mixture is diluted with DCM, filtered and concentrated in vacuo. The reaction mixture is then purified via silica column chromatography with 5% MeOH / CHCl 3 to afford ethyl ester of the title compound. The ethyl ester is then hydrolyzed by the state of Example 160 to give a compound.

Example 186. A = tBOC, G = OH, L = absence, X = 2- (cyclopropylamino) -thiazole-4-yl, Y = 4-methoxyphenyl, Z = hydrogen, j = 3, Compound of formula IV wherein m = s = 1, R 3 = R 4 = hydrogen .

Formation of 4- (2-cyclopropylamino-thiazole-4-yl) -5- (4-methoxy-phenyl) -2H-pyridazin-3-one (186 hours)

Figure 112005043726247-pct00710

186A. A mixture of commercially available 4,5-dichloropyridazine3 (2H) -one (18 mmol), benzyl bromide (19 mmol), potassium carbonate (45 mmol), tetrabutylrammonium bromide (1 mmol), acetonitrile (45 mL) was prepared. Stir and heat under reflux for 1 hour. After cooling, the solvent is evaporated under reduced pressure. The residue is purified by filtration on a small silica gel column eluting with 10% EtOAc / hexanes to give mixture 186a as a white powder (81%). [M + H] + = 256.3

186B. At room temperature, to a magnetically stirred solution 186a (4.5 mmol) in dry dioxane (20 mL) is added 1.0 mL of 21 wt% sodium methoxide solution. After 1 h, the mixture is taken up in water / ethyl acetate and the organic layer is dried over MgSO 4 and concentrated to an oil. The oil residue is purified by column chromatography eluting with 10% EtOAc / Hex. [M + H] + = 251.7

By using MeOH in addition to dioxane as a solvent, pyridazinone 186a can be obtained instead, with methoxy occupying 5 positions on the pyridazinone ring and chloro occupying 4 positions.

186C. Pyridazinone 186b (1 mmol) is dissolved in DME. To the mixture is added Pd (PPh 3 ) 4 (10 mol%), and the mixture is stirred at room temperature for 10 minutes before adding 4 mL of 4 methoxybenzeneboric acid ( 2 mmol) and 1 mL aqueous solution of Na 2 CO 3 (10 wt%). . The reaction mixture is then heated to reflux for 18 hours. The cooled reaction mixture is diluted with water and extracted three times with ethyl acetate. The composite organic layer is dried (MgSO 4 ), filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with 15% EtOAc / hexanes. [M + H] + = 323.3

186D. 186c solution (3 mmol) of DME is added to 2N KOH and the resulting mixture is heated to reflux for 1 hour. The cooled mixture is diluted with water, oxidized to pH-5 with solid citric acid and extracted three times with CH 2 Cl 2 . The organic layer is washed once with brine, dried (MgSO 4 ), filtered and concentrated in vacuo to give compound 186d. [M + H] + = 309.3

186E. To a cooled solution of compound 186d (2 mmol), triethylamine (0.4 mL) in dichloromethane (10 mL) (ice-acetone bath), add dropwise anhydrous trifluoromethane sulfonic (0.4 mL) drops. . The resulting solution is stirred at −5 ° C. for 30 minutes. The reaction mixture is then placed in HCl (0.5M) and extracted with CH 2 Cl 2 . The composite compound layer is washed with 1% NaHCO 3 , brine, dried (MgSO 4 ), filtered and concentrated in vacuo to give a brown oil. Compound 186e is used immediately without further purification. [M + H] + = 441.4

186F. Commercially available 2,4-dibromothiazole (2 mmol) is dissolved in cyclopropylamine (3 mL) and the reaction mixture is heated at 50 ° C. for 8 hours. The cooled mixture is then poured into water and extracted twice with ether. 2-cyclopropyl, which is dried over the combined organic portion (MgSO 4 ), evaporates the solvent, is purified by flash column chromatography (silica gel, 15% EtOAc / hexanes) and then converted to the corresponding stannane 186f. Amine-4-bromothiazole is supplied. The 2-cyclopropylamine-4-bromothiazole solution in degassed DME is treated with hexamethylditin and Pd (PPh 3 ) 4 and heated at 80 ° C. for 18 hours. The cooled mixture is concentrated in vacuo and the residue is purified by column chromatography eluting with 20% EtOAc / hexane / 2% Et 3 N to give Stannan 186f. [M + H] + = 304.1

186G. To the degassing solution of compound 186e (1 mmol) and stannane 186f, Pd (PPh 3 ) 4 (10 mol%) is added. The mixture is degassed twice with nitrogen and heated at 100 ° C. for 3 hours. The cooled mixture is concentrated in vacuo and the residue is purified by column chromatography eluting with 30% EtOAc / hexanes to give 186 g of compound. [M + H] + = 431.6

186H. 186 g of compound and 10% Pd / C (wet) in MeOH are hydrogen ballooned for 2 hours. The mixture is filtered through a pad of celite and the filtrate is concentrated in vacuo to give compound 186 h. [M + H] + = 341.4

The title compound is prepared from pyridazinone 186h and the cyclic peptide precursor 1 of Example 1 by the hydrolysis of ethyl ester via the Mitsunobu state of Example 158, and the hydrolysis state described in Example 160 which follows. .

Example 187 A = tBOC, G = OH, L = absent, X and Y = 6-methoxy-isoquinoline- (3, 4) -yl, Z = hydrogen, j = 3, m = s = 1, A compound of formula IV wherein R 3 = R 4 = hydrogen.

Figure 112005043726247-pct00711

187A. Pyridazinone 186b (2 mmol) is dissolved in DME. Pd (PPh 3 ) 4 is added to this mixture and stirred for 10 minutes at room temperature before the addition of 2-formyl-4-methoxybenzene-poronic acid and Na 2 CO 3 (10 wt%). The reaction mixture is then heated to reflux for 18 hours. The cooled reaction mixture is diluted with water and extracted three times with ethyl acetate. The composite organic layer is dried (MgSO 4 ), filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with 20% EtOAc / hexanes to give compound 187a. [M + H] + = 351.4

187B. A mixture of pyridazinone 187a (1 mmol), MeOH (20 mL), NH 4 OH (10 mL, 28-30 wt%) is heated at 60 ° C. for 30 minutes. After cooling, the precipitate, compound 187b, is filtered off and washed with MeOH (15 mL). [M + H] + = 351.4

187C. A mixture of pyridazinoisoquinolinone 187b (0.5 mmol), AlCl 3 , toluene is mixed and heated at 70 ° C. for 1 hour. After cooling, water is added and the mixture is filtered and washed with water. The residue is purified by column chromatography on silica gel eluting with 50% EtOAc / Hex to give compound 187c. [M + H] + = 227.3

The title compound was subjected to hydrolysis of the ethyl ester via the hydrolysis state described in Example 158, followed by the pyridazinoisoquinolinone 187c and the cyclic peptide of Example 1 via the Mitsunobu state of Example 160. Prepared from Precursor 1.

Example 188. A =-(C = O) -OR 1 (R 1 = cyclopentyl), G = OH, L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, Compound of formula IV wherein m = s = 1, R 3 = R 4 = hydrogen .

188a-amine deprotection

0.041 mmol of the title compound of Example 159 is dissolved in 4 ml of a solution of HCl 4M in dioxane and stirred for 1 hour. Reaction residue 188a is concentrated in vacuo.

188b-Chloroformate Reagent

Chloroformate reagent (188b) was prepared by dissolving 0.04 mmol cyclopentanol in THF (3 ml) and 0.09 mmol phosgene in toluene (20%). As a result, the reaction is stirred at room temperature for 2 hours and the solvent is removed in vacuo. DCM was added to the residue and consequently concentrated to dry twice in vacuo to yield chloroformate reagent 188b.

188c-Carbamate Formation

The title carbamate is made by dissolving the residue 188a in 1 ml of THF and adding 0.045 mmol of TEA, as a result of cooling the reaction mixture to 0 ° C. To this 0 ° C. reaction mixture is added 3 ml THF chloroformate reagent (188b). The resulting mixture was reacted at 0 ° C. for 2 hours, extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO 4 , concentrated in vacuo to dryness. . This crude compound is purified on a silica column and then the ethyl ester is hydrolyzed through the treatment described in Example 160.

Example 189. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 = cyclobutyl, G = OH, L = absent, X = Y = thiopen-3- Work, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

The title compound is prepared by the method described in Example 188 with the title compound of Example 159 and cyclobutanol.

Example 190. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 = cyclohexyl, G = OH, L = absent, X = Y = thiophen-3-yl, Z = Hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

 This title compound is prepared by the method described in Example 188 with the title compound of Example 159 and cyclohexanol.

Example 191 A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 =

Figure 112007053853814-pct00712
, G = OH, L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

The title compound is made by the method described in Example 188 with the title compound of Example 159 and (R) -3-hydroxytetrahydrofuran.

Example 192. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 =

Figure 112007053853814-pct00713
, G = OH, L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

The title compound is prepared by the method described in Example 188 with the title compound of Example 159 and (S) -3-hydroxytetrahydrofuran.

Example 193. A compound of Formula II wherein A =-(C = O) -OR 1 , wherein R 1 =

Figure 112007053853814-pct00714
, G = OH, L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

The title compound is combined with the title compound of Example 159.

Figure 112005043726247-pct00715
It is made by the method described in Example 188.

Example 194 A compound of Formula II wherein A =-(C = O) -R 1 , wherein R 1 = cyclopentyl, G = OH, L = absent, X = Y = thiophene-3- Work, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

The title compound is the title compound of Example 159 in 4 ml of 4M hydrochloric acid solution in dioxane, made by stirring the reaction mixture for 1 hour. The reaction residue is concentrated in vacuo. To this residue, 4 ml THF and 0.045 mmol TEA are added, cooled to 0 ° C. and 0.045 mmol of cyclopentyl acid chloride is added. As a result, the reaction mixture is stirred at 0 ° C. for 2 hours. The reaction mixture is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO 4 , concentrated in vacuo to dryness. This crude compound is purified on a silica column and then the ethyl ester is hydrolyzed through the treatment described in Example 160.

Example 195 A compound of Formula II wherein A =-(C = O) -NH-R 1 , wherein R 1 = cyclopentyl, G = OH, L = absent, X = Y = thiophene- 3-day, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

The title compound is the title compound of Example 159 in 4 ml of 4M hydrochloric acid solution in dioxane, made by stirring for 1 hour. As a result, the reaction residue is concentrated in vacuo, dissolved in 4 ml THF and cooled to 0 ° C. 0.045 mmol cyclopentyl isocyanate is added to this 0 ° C. solution and the reaction mixture is stirred at RT for 4 h. The solution is extracted with EtOAc, washed with 1% hydrochloric acid, water and brine, dried over MgSO 4 , concentrated in vacuo to dryness. This crude compound is purified on a silica column and then the ethyl ester is hydrolyzed through the treatment described in Example 160.

Example 196 A compound of Formula II wherein A =-(C = S) -NH-R 1 , wherein R 1 = cyclopentyl, G = OH, L = absent, X = Y = thiophene- 3-day, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

The title compound is the title compound of Example 159 in 4 ml of 4M hydrochloric acid solution in dioxane, made by stirring for 1 hour. As a result, the reaction residue is concentrated in vacuo, dissolved in 4 ml THF and cooled to 0 ° C. To this 0 ° C. solution is added 0.045 mmol cyclopentyl isothiocyanate and the resulting reaction mixture is stirred at RT for 4 h. The solution is then extracted with EtOAc, washed with 1% hydrochloric acid, water and brine, dried over MgSO 4 , concentrated in vacuo to dryness. This crude compound is purified by silica column and then the ethyl ester is hydrolyzed via the treatment described in Example 160.

Example 197. A compound of formula II wherein A = -S (O) 2 -R 1 , wherein R 1 = cyclopentyl, G = OH, L = absent, X = Y = thiophene-3- Work, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

The title compound is the title compound of Example 159 in 4 ml of 4M hydrochloric acid solution in dioxane, made by stirring for 1 hour. The resulting concentrated reaction residue, which was dissolved in 4 ml THF, was cooled to 0 ° C. with 0.045 mmol TEA added. To this 0 ° C. solution, 0.045 mmol cyclopentyl sulfonyl chloride is added and the reaction mixture is stirred at 0 ° C. for 2 hours. The solution is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO 4 , concentrated in vacuo to dryness. This crude compound is purified by silica column and then the ethyl ester is hydrolyzed via the treatment described in Example 160.

Example 198. A compound of Formula II wherein A =-(C = O) -OR 1 , R 1 = cyclopentyl, G = -O-pentethyl, L = absent, X = Y = thiophene -3-yl, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

Figure 112005043726247-pct00716

The title compound was added to the title compound of Example 194 and a solution of phenethyl alcohol (198a) in 0.5 ml DCM, 1.2 eq. PyBrOP, 4eq. DIEA and catalytic reaction amount of DMAP are made by addition at 0 ° C. As a result, the reaction mixture is stirred at 0 ° C. for 1 hour and then warmed up to room temperature (RT) over 4-12 hours. The reaction mixture was purified by silica gel flash chromatography using different nucleic acid: EtOAc ratios (9: 1 → 5: 1 → 3: 1 → 1: 1) as the elution phase to give the title compound free pen. Ethyl ester (198b) is provided.

Other esters can also be made using the same treatments.

Example 199 A compound of Formula II, wherein A =-(C = O) -OR 1 , R 1 = cyclopentyl, G = -NH-pentethyl, L = absent, X = Y = thiophene -3-yl, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

Figure 112005043726247-pct00717

The title compound is prepared by adding EDC (1.2 eq.) And DIEA (4 eq.) At 0 ° C. to the title compound of Example 194 and a solution of phenethylamine (199a) (0.05 ml) in 0.5 ml DMF. As a result, the reaction mixture is stirred for 1 hour. The reaction is then warmed to room temperature (RT) over 4-12 hours. The reaction mixture was purified by silica gel flash chromatography using different nucleic acid: EtOAc ratios (9: 1 → 5: 1 → 3: 1 → 1: 1) as the elution phase to give the title compound phenethyl amide. Provided 199b.

Other amides can also be made through the same treatments.

Example 200. A compound of Formula II wherein A =-(C = O) -OR 1 , R 1 = cyclopentyl, G = -NHS (O) 2 -phenethyl, L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

Figure 112005043726247-pct00718

The title compound was added to the title compound of Example 194 and a solution of α-toluenesulfonamide (200a) (10 mg) in 0.5 ml DCM, 1.2 eq. PyBrOP, 4 eq. DIEA and catalysis DMAP are added at 0 ° C. As a result, the reaction mixture is stirred for 1 hour and then warmed up to room temperature (RT) over 4-12 hours. The reaction mixture was purified by silica gel flash chromatography using different nucleic acid: EtOAc ratios (9: 1 → 5: 1 → 3: 1 → 1: 1) as the elution phase to give the title compound sulfonamide ( 200b).

Other sulfonamides can also be made through the same treatments.

Example 201 A compound of formula II wherein A =-(C = O) -OR 1 , R 1 = cyclopentyl, G =-(C = O) -OH, L = absent, X = Y = Thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

Figure 112005043726247-pct00719

The title compound is prepared by adding EDC (1.2 eq.) And DIEA (4 eq.) At 0 ° C. to the title compound solution of Example 194 in 0.5 mL DMF. As a result, the reaction mixture is stirred for 1 hour. The reaction is then warmed to room temperature (RT) over 4-12 hours. The reaction mixture is purified by silica gel flash chromatography to give hydroxyamide. The hydroxyamide is then treated with DIBAL-H in THF at −78 ° C. for 2 hours. The reaction mixture is then diluted with 8 ml EtOAc, washed with water and brine, dried over Na 2 S0 4 and concentrated in vacuo to yield aldehyde 201a. To a solution of aldehyde 201a in 0.5 ml THF is added α-hydroxy-α-methyl-propionitrile (0.1 ml) and catalytic reaction amount of TFA at 0 ° C. The resulting reaction mixture is hydrolyzed with concentrated hydrochloric acid in dioxane and then warmed from 0 ° C. to room temperature (RT) for 4-12 hours. The reaction is then extracted with EtOAc and washed with water and brine to yield the α-hydroxy compound 201b in crude form. The crude compound 201b undergoes Dess-Martin oxidation in THF (0.5 ml) to provide the α-carbonyl compound 201c in crude form. The crude compound 201c was purified by silica gel flash chromatography using different hexane: EtOAc ratios (9: 1 → 5: 1 → 3: 1 → 1: 1) as the elution phase to afford the title compound Keto acid 201c is provided.

Example 202. A compound of Formula IV wherein A =-(C = O) -OR 1 , R 1 = cyclopentyl, G =-(C = O) -O-phenethyl, L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

The title compound is made of penethanol and the title compound keto acid of Example 201 according to the treatment described in Example 198.

Example 203. A compound of Formula IV wherein A =-(C = O) -OR 1 , R 1 = cyclopentyl, G =-(C = O) -NH-phenethyl, L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1 and R 3 = R 4 = hydrogen.

The title compound is made of phenethyl amine and the title compound keto acid of Example 201 according to the treatment described in Example 199.

Example 204. Compound of formula IV, wherein A =-(C = O) -O-R One And R One = Cyclopentyl, G =-(C = O) -NH-S (O) 2 -benzyl, L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1 and R 3  = R 4  = Hydrogen.

 The title compound is made of α-toluenesulfonamide and the title compound keto acid of Example 201 according to the treatment described in Example 200.

Example 205. A compound of formula II, wherein A = tBOC, G = OH, L =-(C = O) CH 2- , X = Y = thiophen-3-yl, Z = hydrogen, j = 1, m = s = 1 and R 3  = R 4  = Hydrogen.

The title compound was prepared by 4,5-di (thiophen-3yl) -2H-pyridazine piridazin) -3-one and modified cyclic peptide precursor mesylate formed at 88C.

Example 206. A compound of formula II wherein A = tBOC, wherein G = OH, L = -CH (CH 3 ) CH 2- , X = Y = thiophen-3-yl, Z = hydrogen, j = 1, m = s = 1, R 3  = Methyl and R 4  = Hydrogen.

The title compound was prepared by 4,5-di (thiophen-3yl) -2H-pyridazine (by Mitsunobu conditions described in Example 158, followed by hydrolysis of ethyl ester via the method described in Example 160). piridazin) -3-one and modified cyclic peptide precursor mesylate formed at 89G.

Example 207. A compound of formula II wherein A = tBOC, G = OH, L = -O-, X = Y = thiophen-3-yl, Z = hydrogen, j = 0, m = s = 1, R 3  = Methyl and R 4  = Hydrogen.

The title compound was prepared by 4,5-di (thiophen-3yl) -2H-pyridazine (by Mitsunobu conditions described in Example 158, followed by hydrolysis of ethyl ester via the method described in Example 160). piridazin) -3-one and modified cyclic peptide precursor mesylate formed at 90D.

Example 208. Compound of formula II, wherein A = tBOC, G = OH, L = -S-, X = Y = thiophen-3-yl, Z = hydrogen, j = 0, m = s = 1, R 3  = Methyl and R 4  = Hydrogen.

The title compound was prepared by 4,5-di (thiophen-3yl) -2H-pyridazine (by Mitsunobu conditions described in Example 158, followed by hydrolysis of ethyl ester via the method described in Example 160). piridazin) -3-one and modified cyclic peptide precursor mesylate formed at 91E.

Example 209. Compound of formula II, wherein A = tBOC, G = OH, L = -S (O)-, X = Y = thiophen-3-yl, Z = hydrogen, j = 2, m = s = 1, R 3  = Methyl and R 4  = Hydrogen.

The title compound was prepared by 4,5-di (thiophen-3yl) -2H-pyridazine (by Mitsunobu conditions described in Example 158, followed by hydrolysis of ethyl ester via the method described in Example 160). piridazin) -3-one and a modified cyclic peptide precursor mesylate formed at 92B.

Example 210. A compound of formula II, wherein A = tBOC, G = OH, L = -S (O) 2 , X = Y = thiophen-3-yl, Z = hydrogen, j = 2, m = s = 1, R 3  = Methyl and R 4  = Hydrogen.

The title compound was prepared by 4,5-di (thiophen-3yl) -2H-pyridazine (by Mitsunobu conditions described in Example 158, followed by hydrolysis of ethyl ester via the method described in Example 160). piridazin) -3-one and a modified cyclic peptide precursor mesylate formed at 93B.

Example 211. Compound of formula II, wherein A = tBOC, G = OH, L = -SCH 2 CH 2- , X = Y = thiophen-3-yl, Z = hydrogen, j = 0, m = s = 1 and R 3  = R 4 = CH 3 .

The title compound was prepared by 4,5-di (thiophen-3yl) -2H-pyridazine (by Mitsunobu conditions described in Example 158, followed by hydrolysis of ethyl ester via the method described in Example 160). piridazin) -3-one and a modified cyclic peptide precursor mesylate formed at 94B.

Example 212. Compound of formula II, wherein A = tBOC, G = OH, L = CF 2 CH 2 , X = Y = thiophen-3-yl, Z = hydrogen, j = 1, m = s = 1 and R 3  = R 4  = Hydrogen.

The title compound was prepared by 4,5-di (thiophen-3yl) -2H-pyridazine (by Mitsunobu conditions described in Example 158, followed by hydrolysis of ethyl ester via the method described in Example 160). piridazin) -3-one and modified cyclic peptide precursor mesylate formed at 95C.

Example 213. A compound of formula II wherein A = tBOC, G = OH, L = -CHFCH 2- , X = Y = thiophen-3-yl, Z = hydrogen, j = 1, m = s = 1 and R 3  = R 4  = Hydrogen.

The title compound was prepared by 4,5-di (thiophen-3yl) -2H-pyridazine (by Mitsunobu conditions described in Example 158, followed by hydrolysis of ethyl ester via the method described in Example 160). piridazin) -3-one and modified cyclic peptide precursor mesylate formed at 96C.

Example 214. Compound of formula III wherein A = tBOC, where G = OH, L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1 and R 3  = R 4  = Hydrogen.

214A. Saturated cyclic peptide precursors are made by catalytic reduction of the mesylate cyclic peptide precursor of Example 2 with Pd / C in MeOH in an H 2 atmosphere.

The title compound was prepared by 4,5-di (thiophen-3yl) -2H-pyridazine (by Mitsunobu conditions described in Example 158, followed by hydrolysis of ethyl ester via the method described in Example 160). piridazin) -3-one and saturated cyclic peptide precursor mesylate formed at 214A.

Compounds of the present invention exhibit strong inhibitory properties against HCV NS3 proteinase. The examples below illustrate exemplary assays for testing compounds of the invention for anti-HCV effects.

Example 215. NS3 / NS4a Protease Enzyme Assay

HCV proteinase activity and inhibition are analyzed using an internally quenched fluorogenic substrate. DABCYL and EDANS groups are attached to opposite ends of the short peptide. Quenching of EDANS fluorescence by the DABCYL group is released by proteolytic cleavage. Fluorescence is measured using a Molecular Device Fluoromax (or equivalent) using an excitation wavelength of 355 nm and an emission wavelength of 485 nm.

The assay was introduced by introducing a white half-region 96-well plate (VWR 29444-312 [Coming 3693]) with full length NS3 HCV proteinase 1b bound with NS4A cofactor (final enzyme concentration 1-15 nM). Proceed. The assay buffer is supplemented with 10 μM NS4A Qualifier Pep 4A (Anaspec 25336 or in-house, MW 1424.8). RET S1 (Ac-Asp-Glu-Asp (EDANS) -Glu-Glu-Abu- [COO] Ala-Ser-Lys- (DABCYL) -NH 2 , AnaSpec 22991, MW 1548.6) is a fluorogenic peptide Used as a substrate. The assay buffer contained 50 mM Hepes, 30 mM NaCl and 10 mM BME at pH 7.5. The enzymatic reaction then takes place over 30 minutes at room temperature in the presence and absence of the inhibitor.

Peptide inhibitor HCV Inh 1 (Anaspec 25345, MW 796.8) Ac-Asp-Glu-Met-Glu-Glu-Cys-OH, [-20 ° C.] and HCV Inh 2 (Anaspec 25346, MW 913.1) Ac-Asp-Glu- Dif-Cha-Cys-OH was used as the reference compound.

IC50 values were calculated using XLFit in ActivityBase (IDBS) using equation 205 [y = A + ((B-A) / (1 + ((C / X) ^ D))]].

Example 216. Cell-Based Replicon Assay

Quantification of HCV Replicon RNA in Cell Lines (HCV Cell Based Analysis)

Cell lines including Huh-11-7 or Huh 9-13 with HCV replicon (Lohmann, et al Science 285: 110-113, 1999) were introduced into 96 well plates at 5 × 10 3 cells / well and fed Fed media was intended to contain DMEM (high glucose), 10% calf fetal serum, penicillin-streptomycin and essential amino acids. Cells were incubated at 37 ° C. in a 5% CO 2 incubator. At the end of the incubation period, total RNA was extracted and purified from cells using the Qiagen Rneasy 96 Kit (Catalog No. 74182). To amplify the HCV RNA so that sufficient material can be detected by the HCV specific probe (described below), the HCV specific primer (described below) is a Tagman One-Step RT-PCR Master Mix Kit (TaqMan One-Step). Mediation of both cDNA and reverse transcription of HCV RNA is mediated by polymerase chain reaction (PCR) using RT-PCR Master Mix Kit (Applied Biosystems catalog no. 4309169). The nucleotide sequence of the RT-PCT primer located in the NS5B region of the HCV genome is as follows:

HCV anterior primer "RBNS5bfor"

5'GCTGCGGCCTGTCGAGCT:

HCV reverse primer "RBNS5Brev":

5'CAAGGTCGTCTCCGCATAC

Detection of RT-PCR products was performed with an Applied Biosystems (ABI) Prism 7700 Sequence Detection System that detects fluorescence that is emitted when probes labeled with fluorescent reporter dyes and quencher dyes are processed during the PCR reaction. ) Prism 7700 Sequence Detection System (SDS). The increase in fluorescence is measured during each cycle of PCR, which reflects an increase in the amount of RT-PCR product. Specifically, quantitation is based on a threshold cycle in which the amplification graph crosses a threshold of a given fluorescence. Comparison of the threshold cycles of a sample with known standards provides a sensitive measurement of the relative template concentration in different samples (ABI User Bulletin # 2 December 11, 1997). The data is analyzed using ABI SDS Program Version 1.7. Relative template concentrations can be converted to RNA copy numbers by using standard curves of HCV RNA standards with known copy numbers (ABI User Bulletin # 2 December 11, 1997).

RT-PCR products were detected using the following labeled probes:

5'FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA

FAM = fluorescent reporter dye.

TAMRA: = Quiner Dye.

The RT reaction is carried out at 48 ° C. for 30 minutes, followed by PCR. The thermal cycler parameters used for the PCR reactions in the ABI Prism 7700 Sequence Detection System were 1 cycle at 95 ° C. for 10 minutes, followed by 1 cycle of primary culture at 95 ° C. for 15 seconds and 1 minute at 60 ° C. It was 35 cycles including the secondary culture of.

To normalize data for internal control molecules in cellular RNA, RT-PCT is performed on cell messenger RNA glyceraldehyde-3-phosphate dehydrogenase (GAPDH). GAPDH copy numbers are very stable in the cell lines used. GAPDH RT-PCR is performed on the same exact RNA sample with HCV copy number determined. Standards for determining copy number as well as GAPDH primers and probes are contained in the ABI Pre-Developed TaqMan Assay Kit (catalog no. 4310884E). The ratio of HCV / GAPDH RNA is used to calculate the activity of the compounds evaluated for inhibition of HCV RNA replication.

Replicon  In a Huh-7 cell line HCV  Activity of compounds as inhibitors of replication (cell based assay)

Effect of specific antiviral compounds on HCV replicon RNA levels in Huh-11-7 or 9-13 cells against GAPDH in cells exposed to compound on cells exposed to 0% inhibition and 100% inhibition control It was measured by comparing the amount of normalized HCV RNA (eg, the ratio of HCV / GAPDH). Specifically, cells were introduced into 96 well plates at 5 × 10 3 cells / well, 1) medium containing 1% DMSO (0% inhibition control), 2) 100 international units in medium / 1% DMSO, IU / ml Interferon-alpha 2b, or 3) were incubated under the conditions of either medium /% DMSO containing a fixed concentration of compound. The 96 well plates described above were then incubated at 37 ° C. for 3 days (first screening assay) or 4 days (IC50 measurement). Percent inhibition was defined as follows:

% Suppression = [100-((S-C2) / C1-C2))] × 100

In the above formula,

S = ratio of HCV RNA copies / GAPDH RNA copies in the sample

Ratio of HCV RNA Copy / GAPDH RNA Copy in C1 = 0% Inhibition Control (Medium / 1% DMSO)

C2 = ratio of HCV RNA copies / GAPDH RNA copies in 100% inhibition control (100 IU / ml interferon-alpha 2b)

Dose-response curves of inhibitors were generated by successive addition of compounds diluted three-fold over three logs into the wells starting with the highest concentration of 10 μM and ending with a concentration of 0.01 μM. In addition, if the IC50 value is not in the straight region of the curve, a dilution series (for example, from 1 μM to 0.001 μM) is executed. IC50 values were defined as A = 100% inhibition value (100 IU / ml interferon-alpha 2b), B = 0% inhibitor value (media / 1% DMSO) and C = (BA / 2) + A. As determined based on the IDBS active base program using Microsoft Excel "WL Fit", which is the median of the C = curve. A, B and C values are expressed as the ratio of HCV RNA / GAPDH RNA as determined for each sample in each well of a 96 well plate as described above. For each well the mean of 4 wells was used to define 100% and 0% inhibition values.

While the invention has been described with respect to various preferred embodiments, it is not so limited, and it will be apparent to those skilled in the art that modifications and variations of the invention are within the spirit and scope of the appended claims. will be.

The compound inhibits serine protease activity, in particular hepatitis C virus (HCV) NS3-NS4A protease. The compounds of the present invention thus interfere with the life cycle of hepatitis C virus and are also useful as antiviral agents. The invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating HCV infection in a subject by administering a pharmaceutical composition comprising a compound of the invention.

Claims (77)

  1.  A compound of formula (I)
    [Formula I]
    Figure 112009026180213-pct00720
    Where
    A is H,-(C = O) -R 2 ,-(C = O) -OR 1 , -C (= O) -NH-R 2 , -C (= S) -NH-R 2 , -S (O) 2 -R 2 ,-(C = NR 1 ) -R 1 and-(C = NR 1 ) -NH-R 1 ;
    G is -OH, -O- (C 1 -C 12 alkyl), -NHS (O) 2 -R 1, - (C = O) -R 1, -C (= O) -OR 1 , and - (C = O) -NH-R 1 ;
    L is -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S (O) CH 2 CH 2- , -O-, -OCH 2- , -OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2- , -CF 2 CH 2- , and -CR x = CR x- , wherein R x = H or halogen;
    j is 0, 1, 2, 3, or 4;
    m is 0, 1, or 2;
    s is 0, 1 or 2;
    R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
    R 2 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl , Substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
    R 3 and R 4 are each independently selected from the group consisting of hydrogen, OH, CH 3 , CN, SH, halogen, NO 2 , NH 2 , amide, methoxy, trifluoromethoxy, and trifluoromethyl;
    E is selected from -CH = CH- or -CH 2 -CH 2- ; Also
    W is:
    (a) an aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having up to 4 ring heteroatoms and 5 to 16 ring atoms selected from O, N and S, wherein the ring system is OH Optionally substituted with up to 3 ring substituents selected from the group consisting of CN, halogen, formyl, R 10 and R 11 ; or
    (b) an aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having up to 4 ring heteroatoms and 5 to 16 ring atoms selected from O, N and S, wherein the ring system is OH Optionally substituted with up to three ring substituents selected from the group consisting of CN, halogen, formyl, and R 10 ;
    here,
    Each R 10 is independently alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl , Arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, heteroaryl or urea, each of which is Silver halogen, OH, alkoxy and perhaloalkyl; C (= 0) -R 11 ; OC (= 0) R 11 ; C (= 0) OR 11 ; C (= 0) N (R 11 ) 2 ; C (= S) N (R 11 ) 2 ; SO 2 R 11 ; NHS (O 2 ) R 11 ; N (R 12 ) 2 ; And N (R 12 ) C (= 0) R 11 optionally substituted with up to 3 groups;
    Each R 11 is independently H, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl , Heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, wherein any of these May be optionally substituted with up to 3 groups selected from halogen, OH, alkoxy and perhaloalkyl;
    Each R 12 is independently H, formyl, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, hetero Arylalkyl, heteroaryl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, or diarylaminoalkyl, wherein any of these are halogen, OH Optionally substituted with up to 3 groups selected from alkoxy and perhaloalkyl;
    In each of the above substituents:
    Aryl is selected from phenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl;
    Heteroaryl is a cyclic aromatic radical having 5 to 10 ring atoms wherein at least one ring atom is selected from S, O and N, and the remaining ring atoms are carbon;
    Heterocycloalkyl is a bi- or tri-cyclic group or non-aromatic 5-, 6- or 7- containing a fused six-membered ring having 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen. To a circle ring, wherein (i) each 5-membered ring has 0 to 1 double bond and each 6-membered ring has 0 to 2 double bonds, and (ii) any nitrogen and sulfur Heteroatoms are not oxidized; (iii) any nitrogen heteroatom is or is not quaternized; (Iv) the heterocycloalkyl may optionally be fused to a benzene ring;
    Each of substituted aryl, substituted arylalkyl, substituted hetero aryl, substituted heteroarylalkyl, and substituted heterocycloalkyl is F, Cl, Br, I, OH, NO 2 , CN, C 1 -C 6 -alkyl -OH, C (O) - ( C 1 -C 6 - alkyl), OCH 2 - (C 3 -C 12 - cycloalkyl), C (O) - aryl, C (O) - heteroaryl, CO 2 -alkyl, CO 2 -aryl, CO 2 -heteroaryl, CONH 2 , CONH- (C 1 -C 6 -alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C 1 -C 6 -Alkyl), OC (O) -aryl, OC (O) -heteroaryl, OCO 2 -alkyl, OCO 2 -aryl, OCO 2 -heteroaryl, OCONH 2 , OCONH- (C 1 -C 6 -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C 1 -C 6 -alkyl), NHC (O) -aryl, NHC (O) -heteroaryl, NHCO 2 -alkyl, NHCO 2 -aryl, NHCO 2 -heteroaryl, NHCONH 2 , NHCONH- (C 1 -C 6 -alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO 2- (C 1 -C 6 alkyl), SO 2 aryl, SO 2 -heteroaryl , SO 2 NH 2, SO 2 NH- (C 1 -C 6 alkyl), SO 2 NH- aryl, SO 2 NH- heteroaryl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl Kiel, CF 3, CH 2 CF 3 , CHCl 2, CH 2 NH 2, CH 2 SO 2 CH 3 H, C 1 -C 6 alkyl, halo alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C 1 -C 6 -alkoxy, methoxymethoxy, methoxy Methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C 1 -C 3 -alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C 1 -C 6 -alkylthio, or methyl One or more substituents independently selected from the group consisting of thiomethyl;
    Arylalkyl is a C 1 -C 3 alkyl or C 1 -C 6 alkyl residue attached to an aryl ring.
  2. delete
  3. delete
  4. The compound of claim 1, wherein W is an aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having up to 4 ring heteroatoms and 5 to 16 ring atoms selected from O, N and S, Wherein said ring system is optionally substituted with up to three ring substituents selected from the group consisting of OH, CN, halogen, formyl, R 10 and R 11 .
  5. The compound of claim 1, wherein W is an aliphatic heteromonocyclic ring system having up to 4 ring heteroatoms and 5 to 7 ring atoms selected from O, N, and S, wherein the ring system is OH, CN, halogen And formyl, optionally substituted with up to 3 ring substituents selected from the group consisting of R 10 and R 11 .
  6.  6. A compound according to claim 5, wherein said optionally substituted aliphatic heteromonocyclic ring system has one or two ring heteroatoms and five ring atoms selected from O, N and S.
  7.  7. The compound of claim 6, wherein said optionally substituted aliphatic heteromonocyclic ring system is pyrrolidine, pyrazolidine, pyrroline, tetrahydrothiophene, dihydrothiophene, tetrahydrofuran, dihydrofuran, imida. A compound selected from the group consisting of sleepy, tetrahydroimidazole, dihydropyrazole, tetrahydropyrazole and oxazoline.
  8.  6. The compound of claim 5, wherein said optionally substituted aliphatic heteromonocyclic ring system has one or two ring heteroatoms and six ring atoms selected from O, N and S.
  9.  9. The compound of claim 8, wherein said optionally substituted aliphatic heteromonocyclic ring system is pyridine, piperidine, dihydropyridine, tetrahydropyridine, dihydropyran, tetrahydropyran, dioxane, piperazine, dihydropyrimidine , Tetrahydropyrimidine, perhydro pyrimidine, morpholine, thioxane and thiomorpholine.
  10.  6. A compound according to claim 5, wherein said optionally substituted aliphatic heteromonocyclic ring system has one or two ring heteroatoms and seven ring atoms selected from O, N and S.
  11.  10. The compound of claim 8, wherein said optionally substituted aliphatic heteromonocyclic ring system is selected from the group consisting of hexamethyleneimine and hexamethylene sulfide.
  12. The aliphatic heterobicyclic ring system of claim 1, wherein W is an aliphatic heterobicyclic ring system having up to 4 ring heteroatoms and 5 to 16 ring atoms selected from O, N and S, wherein the ring system is OH, CN, halogen , Formyl, and R 10 optionally substituted with up to 3 ring substituents.
  13.  13. The compound of claim 12, wherein the optionally substituted aliphatic heterobicyclic ring system has 1 to 4 ring heteroatoms and 8 to 12 ring atoms selected from O, N and S.
  14.  14. The compound of claim 13, wherein said optionally substituted aliphatic heterobicyclic ring system has one or two ring heteroatoms selected from O and N and 8 to 12 ring atoms.
  15. The compound of claim 1, wherein W is an aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having up to 4 ring heteroatoms and 5 to 16 ring atoms selected from O, N and S, Wherein said ring system is optionally substituted with up to three ring substituents selected from the group consisting of OH, CN, halogen, formyl, and R 10 .
  16. 2. The aromatic heteromonocyclic ring system of claim 1, wherein W is an aromatic heteromonocyclic ring system having up to 4 ring heteroatoms and 5 to 7 ring atoms selected from O, N, and S, wherein the ring system is OH, CN, halogen. , Formyl and R 10 optionally substituted with up to 3 ring substituents.
  17.  16. The compound of claim 15, wherein said optionally substituted aromatic heteromonocyclic ring system has one or two ring heteroatoms and five ring atoms selected from O, N and S.
  18.  18. The system of claim 17, wherein the optionally substituted aromatic heteromonocyclic ring system comprises pyrrole, pyrazole, porphyrin, furan, thiophene, pyrazole, imidazole, oxazole, oxadiazole, isoxazole, thiazole, thia Diazoles, and isothiazoles.
  19.  17. The compound of claim 16, wherein said optionally substituted aromatic heteromonocyclic ring system has one, two or three ring heteroatoms and six ring atoms selected from O, N and S.
  20.  20. The compound of claim 19, wherein said optionally substituted aromatic heteromonocyclic ring system is selected from the group consisting of pyridine, pyrimidine, pyrazine, pyran and triazine.
  21.  17. The compound of claim 16, wherein said optionally substituted aromatic heteromonocyclic ring system has 3 or 4 ring heteroatoms and 5 ring atoms selected from O, N and S.
  22.  22. The compound of claim 21, wherein said optionally substituted aromatic heteromonocyclic ring system is triazolyl or tetrazolyl.
  23. 2. The aromatic heterobicyclic ring system of claim 1, wherein W is an aromatic heterobicyclic ring system having up to 4 ring heteroatoms and 8 to 12 ring atoms selected from O, N, and S, wherein the ring system is OH, CN, halogen , Formyl and R 10 optionally substituted with up to 3 ring substituents.
  24.  The method of claim 23 wherein the optionally substituted aromatic heterobicyclic ring system comprises adenine, azabenzimidazole, azaindole, benzimidazole, benzoisothiazole, benzofuran, benzoisoxazole, benzoxazole, benzothia Diazole, benzothiazole, benzothiene, benzothiophene, carbazole, cinnaline, guanine, imidazopyridine, indazole, indole, isoindole, isoquinoline, phthalazine, purine, pyrrolopyridine, quinazoline, quinoline , Quinoxaline, thianaphthene and xanthine.
  25. 2. The aromatic heterotricyclic ring system of claim 1, wherein W is an aromatic heterotricyclic ring system having up to 4 ring heteroatoms and 10 to 16 ring atoms selected from O, N, and S, wherein the ring system is OH, CN, halogen And formyl, optionally substituted with up to 3 ring substituents selected from the group consisting of R 10 and R 11 .
  26.  26. The system of claim 25, wherein said optionally substituted aromatic heterotricyclic ring system is selected from the group consisting of carbazole, bizenzofuran, psoraren, dibenzothiophene, phenazine, thianthrene, phenanthroline, phenanthridine. Selected compound.
  27.  The compound of claim 1, wherein
    [Formula II]
    Figure 112009026180213-pct00721
    Where
    A is H,-(C = O) -R 2 ,-(C = O) -OR 1 , -C (= O) -NH-R 1 , -C (= S) -NH-R 2 ,,- S (O) 2 -R 2 ,-(C = NR 1 ) -R 1 and-(C = NR 1 ) -NH-R 1 ;
    G is —OH, —O— (C 1 -C 12 alkyl), —NHS (O) 2 —R 1 , — (C═O) —R 2 , —C (═O) —OR 1 , and — ( C = O) -NH-R 2 ;
    L is absent, -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S (O) CH 2 CH 2- , -O-, -OCH 2- , -OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2- , -CF 2 CH 2 -and -CR x = CR x- (wherein R x = H or halogen);
    W is
    Figure 112009026180213-pct00722
    ,
    Figure 112009026180213-pct00723
    ,
    Figure 112009026180213-pct00724
    And
    Figure 112009026180213-pct00725
    Is selected from the group consisting of
    Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ;
    Q 'is selected from the group consisting of absent, -CH 2 -and -NH-;
    Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl;
    j is 0, 1, 2, 3, or 4;
    m is 0, 1, or 2;
    s is 0, 1 or 2;
    R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
    R 2 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, Arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
    R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl.
  28.  The method of claim 27,
    A is-(C = O) -OR 1 ;
    G is hydroxyl;
    L is absent;
    j is 3; m = s = 1, also
    R 3 and R 4 are hydrogen.
  29.  The compound of claim 27, wherein A is — (C═O) —O-tert-butyl;
    G is hydroxyl;
    L is absent;
    j is 3;
    m = s = 1, also
    R 3 and R 4 are hydrogen.
  30. delete
  31.  The method of claim 27,
    A is-(C = O) -O-tert-butyl;
    G is hydroxyl;
    L is absent;
    W is
    Figure 112005043726247-pct00726
    ,
    j is 3; m = s = 1, also
    R 3 and R 4 are hydrogen.
  32.  The compound of claim 27 selected from the group consisting of:
    j = 3; m = s = 1; And A G L W Q Y R 3 , R 4 tBOC OH Absent
    Figure 112007053853814-pct00727
    Absent Phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00728
    Nonexistence 2-bromophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00729
    Nonexistence 3-bromophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00730
    Nonexistence 4-bromophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00731
    Nonexistence 5-bromo-thienyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00732
    Nonexistence 2-bromo-4-pyridyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00733
    Nonexistence 2-biphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00734
    Nonexistence 3-biphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00735
    Nonexistence 4-biphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00736
    Nonexistence 3- (3-thienyl) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00737
    Nonexistence 3- (p-trifluoromethoxyphenyl) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00738
    Nonexistence 3- (p-cyanophenyl) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00739
    Nonexistence 4- (3-thienyl) phenyl R 3 = R 4 = H;
    j = 3; m = s = 1; And A G L W Q Y R 3 , R 4 tBOC OH Nonexistence
    Figure 112007053853814-pct00740
    Nonexistence 4- (p-trifluoromethoxyphenyl) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00741
    Nonexistence 4- (p-cyanophenyl) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00742
    Nonexistence 5-phenyl-2-thienyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00743
    Nonexistence 5-phenyl-3-pyridyl R 3 = R 4 = H;
    tBOC OEt Nonexistence
    Figure 112007053853814-pct00744
    Nonexistence 3-chloro-4-hydroxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00745
    Nonexistence 3-chloro-4-hydroxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00746
    Nonexistence 3-bromo-4-hydroxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00747
    Nonexistence 2-methyl-4-bromophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00748
    Nonexistence 3-methyl-4-bromophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00749
    Nonexistence n-propyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00750
    Nonexistence n-butyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00751
    Nonexistence 4-ethoxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00752
    Nonexistence 4-propoxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00753
    Nonexistence 4-butoxyphenyl R 3 = R 4 = H;
    j = 3; m = s = 1; And A G L W Q Y R 3 , R 4 tBOC OH Nonexistence
    Figure 112007053853814-pct00754
    Nonexistence 3-methoxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00755
    Nonexistence 3,4-dimethoxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00756
    Nonexistence 4-methoxy-1-naphthyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00757
    Nonexistence 4-phenoxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00758
    Nonexistence benzyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00759
    Nonexistence p-phenylbenzyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00760
    Nonexistence 3-chlorophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00761
    Nonexistence 3-fluorophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00762
    Nonexistence 3-methoxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00763
    Nonexistence 3-phenoxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00764
    Nonexistence 3-benzyloxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00765
    Nonexistence 3-trifluoromethylphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00766
    Nonexistence 4-bromophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00767
    Nonexistence 4-fluorophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00768
    Nonexistence 4-methoxyphenyl R 3 = R 4 = H;
    j = 3; m = s = 1; And A G L W Q Y R 3 , R 4 tBOC OH Nonexistence
    Figure 112007053853814-pct00769
    Nonexistence 4-ethoxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00770
    Nonexistence 4-trifluoromethylphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00771
    Nonexistence 3,5-di (trifluoromethyl) phenyl) R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00772
    Nonexistence 4- (N, N-dimethylamino) -3,5-di (trifluoromethyl) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00773
    Nonexistence 2,4-dichlorophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00774
    Nonexistence 3,5-dichlorophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00775
    Nonexistence 3,4-dichlorophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00776
    Nonexistence 2-pyridyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00777
    Nonexistence 2-pyridyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00778
    Nonexistence 3-pyridyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00779
    Nonexistence 4-pyridyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00780
    Nonexistence 4-methoxy-3-bromophenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00781
    Nonexistence 4- (methylcyclopropane) phenyl R 3 = R 4 = H;
    j = 3; m = s = 1; And A G L W Q Y R 3 , R 4 tBOC OH Nonexistence
    Figure 112007053853814-pct00782
    Nonexistence 3-chloro-4- (methylcyclopropane) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00783
    Nonexistence 3-chloro-4-methoxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00784
    Nonexistence 3-chloro-4-ethoxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00785
    Nonexistence 3-bromo-4-ethoxyphenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00786
    Nonexistence 3-chloro-4- (2-hydroxyethoxy) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00787
    Nonexistence 3-bromo-4- (2-hydroxyethoxy) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00788
    Nonexistence 3-chloro-4- (O-allyl) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00789
    Nonexistence 3-bromo-4- (O-allyl) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00790
    Nonexistence 3-chloro-4- (O-CH 2 SCH 3 ) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00791
    Nonexistence 3-chloro-4- (O-CH 2 SCH 3 ) phenyl R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00792
    Q '= -CH 2-
    Figure 112007053853814-pct00793
    R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00794
    Q '= -CH 2-
    Figure 112007053853814-pct00795
    R 3 = R 4 = H;
  33.  The compound of claim 27 selected from the group consisting of:
    j = 3; m = s = 1; And A G L W Q Y R 3 , R 4 -(C = O) -OR 1 where R 1 = cyclopentyl OH Nonexistence
    Figure 112009026180213-pct00796
    Nonexistence Phenyl R 3 = R 4 = H;
    -(C = O) -OR 1 where R 1 = cyclobutyl OH Nonexistence
    Figure 112009026180213-pct00797
    Nonexistence Phenyl R 3 = R 4 = H;
    A =-(C = O) -OR 1 where R 1 = cyclohexyl OH Nonexistence
    Figure 112009026180213-pct00798
    Nonexistence Phenyl R 3 = R 4 = H;
    A =-(C = O) -OR 1 where R 1 =
    Figure 112009026180213-pct00799
    OH Nonexistence
    Figure 112009026180213-pct00800
    Nonexistence Phenyl R 3 = R 4 = H;
    A =-(C = O) -OR 1 where R 1 =
    Figure 112009026180213-pct00801
    OH Nonexistence
    Figure 112009026180213-pct00802
    Nonexistence Phenyl R 3 = R 4 = H; And
    A =-(C = O) -OR 1 where R 1 =
    Figure 112009026180213-pct00803
    OH Nonexistence
    Figure 112009026180213-pct00804
    Nonexistence Phenyl R 3 = R 4 = H;
  34.  The compound of claim 27 selected from the group consisting of:
    m = s = 1; And A G L W Q Y j m, s R 3 , R 4 tBOC OH -(C = O) CH 2-
    Figure 112007053853814-pct00805
    Nonexistence Phenyl One m = s = 1 R 3 = R 4 = H;
    tBOC OH -CH (CH 3 ) CH 2-
    Figure 112007053853814-pct00806
    Nonexistence Phenyl One m = s = 1 R 3 = methyl R 4 = H;
    tBOC OH -O-
    Figure 112007053853814-pct00807
    Nonexistence Phenyl 0 m = s = 1 R 3 = methyl R 4 = H;
    tBOC OH -S-
    Figure 112007053853814-pct00808
    Nonexistence Phenyl 0 m = s = 1 R 3 = methyl R 4 = H;
    tBOC OH -S (O)-
    Figure 112007053853814-pct00809
    Nonexistence Phenyl 0 m = s = 1 R 3 = methyl R 4 = H;
    tBOC OH -S (O) 2-
    Figure 112007053853814-pct00810
    Nonexistence Phenyl 0 m = s = 1 R 3 = methyl R 4 = H;
    tBOC OH -SCH 2 CH 2-
    Figure 112007053853814-pct00811
    Nonexistence Phenyl 0 m = s = 1 R 3 = R 4 = CH 3 ;
    tBOC OH -CF 2 CH 2-
    Figure 112007053853814-pct00812
    Nonexistence Phenyl One m = s = 1 R 3 = R 4 = H; And
    tBOC OH -CFHCH 2-
    Figure 112007053853814-pct00813
    Nonexistence Phenyl One m = s = 1 R 3 = R 4 = H;
  35. The compound of claim 27 selected from the group consisting of:
    A G L W j m, s R 3 , R 4 -(C = O) -OR 1 R 1 = cyclopentyl -O-phenethyl Nonexistence
    Figure 112007053853814-pct00814
    Q = absent Y = phenyl
    j = 3 m = s = 1 R 3 = R 4 = H;
    -(C = O) -OR 1 R 1 = cyclopentyl -NH-phenethyl Nonexistence
    Figure 112007053853814-pct00815
    Q = absent Y = phenyl
    j = 3 m = s = 1 R 3 = R 4 = H;
    -(C = O) -OR 1 R 1 = cyclopentyl -NHS (O) 2 -phenethyl- Nonexistence
    Figure 112007053853814-pct00816
    Q = absent Y = phenyl
    j = 3 m = s = 1 R 3 = R 4 = H;
    -(C = O) -OR 1 R 1 = cyclopentyl -(C = O) -OH Nonexistence
    Figure 112007053853814-pct00817
    Q = absent Y = phenyl
    j = 3 m = s = 1 R 3 = R 4 = H;
    -(C = O) -OR 1 R 1 = cyclopentyl -(C = O) -O-phenethyl Nonexistence
    Figure 112007053853814-pct00818
    Q = absent Y = phenyl
    j = 3 m = s = 1 R 3 = R 4 = H;
    -(C = O) -OR 1 R 1 = cyclopentyl -(C = O) -NH-phenethyl Nonexistence
    Figure 112007053853814-pct00819
    Q = absent Y = phenyl
    j = 3 m = s = 1 R 3 = R 4 = H;
    -(C = O) -OR 1 R 1 = cyclopentyl -(C = O) -NH-S (O) 2 -benzyl Nonexistence
    Figure 112007053853814-pct00820
    Q = absent Y = phenyl
    j = 3 m = s = 1 R 3 = R 4 = H;
  36. The compound of claim 1, wherein
    [Formula III]
    Figure 112009026180213-pct00821
    Where
    A is H,-(C = O) -R 2 ,-(C = O) -OR 1 , -C (= O) -NH-R 2 , -C (= S) -NH-R 2 , -S (O) 2 -R 2 ,-(C = NR 1 ) -R 1 and-(C = NR 1 ) -NH-R 1 ;
    G is —OH, —O— (C 1 -C 12 alkyl), —NHS (O) 2 —R 1 , — (C═O) —R 2 , —C (═O) —OR 1 , and — ( C = O) -NH-R 2 ;
    L is absent, -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S (O) CH 2 CH 2- , -O-, -OCH 2- , -OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2- , -CF 2 CH 2 -and -CR x = CR x- (wherein R x = H or halogen);
    W is
    Figure 112009026180213-pct00822
    ,
    Figure 112009026180213-pct00823
    ,
    Figure 112009026180213-pct00824
    And
    Figure 112009026180213-pct00825
    Is selected from the group consisting of
    Q is absent, is selected from the group consisting of -CH 2- , -O-, -NH-, -N (R 1 )-, -S-, -S (O 2 )-and-(C = O)- ;
    Q 'is selected from the group consisting of absent, -CH 2 -and -NH-;
    Y is H, C 1 -C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted hetero Selected from the group consisting of cycloalkyl;
    j is 0, 1, 2, 3, or 4;
    m is 0, 1, or 2;
    s is 0, 1 or 2;
    R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
    R 2 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, Arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
    R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl.
  37.  The method of claim 36,
    A is-(C = O) -OR 1 ;
    G is hydroxyl;
    L is absent;
    j is 3;
    m = s = 1, also
    R 3 and R 4 are hydrogen.
  38.  37. The compound of claim 36, wherein A is-(C = 0) -0-tert-butyl;
    G is hydroxyl;
    L is absent;
    j is 3;
    m = s = 1, also
    R 3 and R 4 are hydrogen.
  39.  The method of claim 36,
    A is-(C = O) -OR 1 ;
    G is hydroxyl;
    L is absent;
    W is
    Figure 112005043726247-pct00826
    ,
    j is 3;
    m = s = 1, also
    R 3 and R 4 are hydrogen.
  40.  The method of claim 36,
    A is-(C = O) -O-tert-butyl;
    G is hydroxyl;
    L is absent;
    W is
    Figure 112005043726247-pct00827
    ,
    j is 3;
    m = s = 1, also
    R 3 and R 4 are hydrogen.
  41. The compound of formula (II) of claim 1.
    [Formula II]
    Figure 112009026180213-pct00828
    Where
    A is H,-(C = O) -R 2 ,-(C = O) -OR 1 , -C (= O) -NH-R 2 , -C (= S) -NH-R 2 , -S (O) 2 -R 2 ,-(C = NR 1 ) -R 1 and-(C = NR 1 ) -NH-R 1 ;
    G is —OH, —O— (C 1 -C 12 alkyl), —NHS (O) 2 —R 1 , — (C═O) —R 2 , —C (═O) —OR 1 , and — ( C = O) -NH-R 2 ;
    L is absent, -S-, -SCH 2- , -SCH 2 CH 2- , -S (O) 2- , -S (O) 2 CH 2 CH 2- , -S (O)-, -S (O) CH 2 CH 2- , -O-, -OCH 2- , -OCH 2 CH 2 -,-(C = O) -CH 2- , -CH (CH 3 ) CH 2- , -CFHCH 2- , -CF 2 CH 2 -and -CR x = CR x- (wherein R x = H or halogen);
    W is
    Figure 112009026180213-pct01034
    And
    Figure 112009026180213-pct01035
    Is selected from the group consisting of
    Wherein X and Y are independently H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -CH 2 -alkylamino, -CH 2 -dialkylamino, -CH 2 -arylamino, -CH 2 -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, Substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; Or X and Y are taken together with the carbon atoms occupying positions 4 and 5 of the triazole ring to form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
     j is 0, 1, 2, 3, or 4;
    m is 0, 1, or 2;
    s is 0, 1 or 2;
    R 1 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
    R 2 is H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, substituted C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, Arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
    R 3 and R 4 are each independently selected from the group consisting of hydrogen and methyl.
  42.  42. The method of claim 41 wherein
    A is-(C = O) -OR 1 ;
    G is hydroxyl;
    L is absent;
    j is 3;
    m = s = 1, also
    R 3 and R 4 are hydrogen.
  43.  The compound of claim 41, wherein A is — (C═O) —O-tert-butyl;
    G is hydroxyl;
    L is absent;
    j is 3;
    m = s = 1, also
    R 3 and R 4 are hydrogen.
  44.  42. The method of claim 41 wherein
    A is-(C = O) -OR 1 ;
    G is hydroxyl;
    L is absent;
    W is
    Figure 112005043726247-pct00831
    ,
    j is 3;
    m = s = 1, also
    R 3 and R 4 are hydrogen.
  45.  42. The method of claim 41 wherein
    A is-(C = O) -O-tert-butyl;
    G is hydroxyl;
    L is absent;
    W is
    Figure 112005043726247-pct00832
    ,
    j is 3;
    m = s = 1, also
    R 3 and R 4 are hydrogen.
  46.  42. The compound of claim 41, selected from the group consisting of:
    A G L W J m, s R 3 , R 4 tBOC OH Nonexistence
    Figure 112007053853814-pct00833
    X = Y = phenyl
     j = 3 m = s = 1 R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00834
    X = Y = phenyl
     j = 3 m = s = 1 R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00835
    X = n-propyl Y = phenyl
     j = 3 m = s = 1 R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00836
    X = m-methoxyphenyl Y = p-methoxyphenyl
     j = 3 m = s = 1 R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00837
    X = m-bromophenyl Y = p-methoxyphenyl
     j = 3 m = s = 1 R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00838
    X = 1-naphthyl Y = p-methoxyphenyl
     j = 3 m = s = 1 R 3 = R 4 = H;
    tBOC OH Nonexistence
    Figure 112007053853814-pct00839
    X = 2-thienyl Y = p-phenoxyphenyl
     j = 3 m = s = 1 R 3 = R 4 = H;
    A G L W J m, s R 3 , R 4 tBOC OH Nonexistence